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Hemichorea is a rare complication of non-ketotic hyperglycaemia. Patients with this syndrome have classically longstanding, poorly controlled diabetes. Here, we report a patient presenting hemichorea without diabetic history. His symptom resolved rapidly after correction of hyperglycaemia. We suggest that hemichorea may be the first manifestation of undiagnosed diabetes. [ABSTRACT FROM AUTHOR]

Representation of the environment by hippocampal populations is known to drift even within a familiar environment, which could reflect gradual changes in single-cell activity or result from averaging across discrete switches of single neurons. Disambiguating these possibilities is crucial, as they each imply distinct mechanisms. Leveraging change point detection and model comparison, we find that CA1 population vectors decorrelate gradually within a session. In contrast, individual neurons exhibit predominantly step-like emergence and disappearance of place fields or sustained changes in within-field firing. The changes are not restricted to particular parts of the maze or trials and do not require apparent behavioral changes. The same place fields emerge, disappear, and reappear across days, suggesting that the hippocampus reuses pre-existing assemblies, rather than forming new fields de novo. Our results suggest an internally driven perpetual step-like reorganization of the neuronal assemblies., Competing Interests: Declaration of interests G.B. is a member of the advisory board of Neuron., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neurons in the hippocampus are correlated with different variables, including space, time, sensory cues, rewards, and actions, where the extent of tuning depends on ongoing task demands. However, it remains uncertain whether such diverse tuning corresponds to distinct functions within the hippocampal network or if a more generic computation can account for these observations. To disentangle the contribution of externally driven cues versus internal computation, we developed a task in mice where space, auditory tones, rewards, and context were juxtaposed with changing relevance. High-density electrophysiological recordings revealed that neurons were tuned to each of these modalities. By comparing movement paths and action sequences, we observed that external variables had limited direct influence on hippocampal firing. Instead, spiking was influenced by online action plans modulated by goal uncertainty. Our results suggest that internally generated cell assembly sequences are selected and updated by action plans toward deliberate goals. The apparent tuning of hippocampal neuronal spiking to different sensory modalities might emerge due to alignment to the afforded action progression within a task rather than representation of external cues.

Colorectal cancer (CRC) is one of the most common cancers diagnosed in the world. Although environmental and genetic factors play a major role in the pathogenesis of CRC, extensive research has suggested that vitamin D may play a pivotal role in the development of CRC. Vitamin D, primarily obtained through sunlight exposure, dietary sources, and supplements, has long been recognized for its essential functions in maintaining health, including immune regulation. This article delves into the intricate relationship between vitamin D, the immune system, gut flora, and the prevention of CRC. It presents a synthesis of epidemiological data, experimental studies, and clinical trials, highlighting the mechanisms by which vitamin D influences immune cell function, cytokine production, and inflammation. By enhancing the immune system's surveillance and anti-tumor activity, vitamin D may offer a promising avenue for CRC prevention. Furthermore, this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain. Additionally, the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC, emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms, encompassing antineoplastic mechanisms, influences on the immune system, and modulation of the gut microbiome., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Long COVID, also known as Post-COVID-19 syndrome, is characterized by multisystemic symptoms that persists for weeks to years beyond acute infection. It disproportionately affects women and those with pre-existing anxiety/depression, conditions more prevalent in females. The vagus nerve, with its extensive innervation and regulation of critical bodily functions, has become a focal point for therapeutic interventions. Transcutaneous vagus nerve stimulation (t-VNS) has emerged as a promising non-invasive treatment for COVID-19 conditions., Methods: This pilot study assessed the efficacy of t-VNS in 24 female Long COVID patients (45.8 ± 11.7 years old; 20.2 ± 7.1 months since infection), who underwent a 10-day t-VNS intervention at home (30 min/session, twice a day). Cognition was considered the primary outcome, with anxiety, depression, sleep, fatigue, and smell as secondary outcomes. Outcomes were measured at baseline, post-intervention, and 1-month follow-up., Results: Significant improvements were observed in various cognitive functions, anxiety, depression, and sleep at post-intervention, with benefits remaining or progressing at 1-month follow-up. Improvements in fatigue were delayed, reaching statistical significance at 1-month follow-up compared to baseline. No significant changes were noted in olfactory performance., Conclusion: This pilot study provides preliminary evidence supporting the potential of t-VNS as a therapeutic intervention for female Long COVID patients. The encouraging results justify further rigorous investigation through larger, randomized controlled trials to confirm the efficacy of t-VNS, assess its generalizability to male cohorts, and explore biological markers to inform personalized treatment approaches. Our findings support the allocation of resources to conduct such trials and advance the understanding of t-VNS as a potential treatment for Long COVID., 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 Zheng, Simonian, Wang and Rosario.)

Urinary tract infections (UTIs) are prevalent and recurrent bacterial infections that affect individuals worldwide, posing a significant burden on healthcare systems. The present study aimed to explore the epidemiology of UTIs, investigating the seasonal, gender-specific and age-related bacterial pathogen distribution to guide clinical diagnosis. Data were retrospectively collected from electronic medical records and laboratory reports of 926 UTIs diagnosed in Fuding Hospital (Fujian University of Traditional Chinese Medicine, Fuding, China). Bacterial isolates were identified using standard microbiological techniques. χ 2 tests were performed to assess associations between pathogens and the seasons, sex and age groups. Significant associations were found between bacterial species and seasons. Enterococcus faecium exhibited a substantial prevalence in spring (χ 2 , 12.824; P=0.005), while Acinetobacter baumannii demonstrated increased prevalence in autumn (χ 2 , 16.404; P=0.001). Female patients showed a higher incidence of UTIs. Gram-positive bacteria were more prevalent in males, with Staphylococcus aureus showing significant male predominance (χ 2 , 14.607; P<0.001). E. faecium displayed an age-related increase in prevalence (χ 2 , 17.775; P<0.001), whereas Escherichia coli tended to be more prevalent in younger patients (χ 2 , 12.813; P=0.005). These findings highlight the complex nature of UTIs and offer insights for tailored diagnostic and preventive strategies, potentially enhancing healthcare outcomes., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024, Spandidos Publications.)

To explore the formation mechanism of the ozone （O 3 ） and emission reduction strategy in a northwestern city， an extensive field campaign was conducted in summertime in 2021 in Yining City， in which the 0-D box model incorporating the latest explicit chemical mechanism （MCMv3.3.1） was applied for the first time to quantify the O 3 -NO x -VOCs sensitivity and formulate a precise O 3 control strategy in this city. The results showed that： ① the three indicators ［i.e.， O 3 formation potential （OFP）， ·OH reaction rate （ k ·OH ）， and relative incremental reactivity （RIR）］ jointly indicated that alkenes， oxygenated volatile organic compounds （OVOCs）， and aromatics were the highest contributors among anthropogenic volatile organic compounds （AVOC） to O 3 formation， and the contribution of biogenic volatile organic compounds （BVOC） also could not be ignored. Additionally， the results based on RIR calculation implied that that the acetaldehyde， ethylene， and propylene were the most sensitive individual VOCs species in Yining City. ② The in-situ photochemical O 3 variations were primarily influenced by the local photochemical production and export process horizontally to downwind areas or vertically to the upper layer， and the reaction pathways of HO 2 ·+ NO and ·OH + NO 2 contributed the most to the gross O x photochemical production （60%） and photochemical destruction production （53%）， respectively. Hence， the reduction in local emissions for O 3 precursors was more essential to alleviate O 3 pollution in this city. ③ The outcome based on RIR（NO x ） / RIR（AVOC） and EKMA jointly suggested that the photochemical regime in this city can be considered a transitional regime that was also nearly a VOCs-limited regime. Detailed mechanism modeling based on multiple scenarios further suggested that the NO x and VOCs synergic emission reduction strategies was helpful to alleviate O 3 pollution. These results are useful to provide policy-related guidance for other cities facing similar O 3 pollution in northwest China.

Aimed to explore the relationships between infection localization, bacterial species, and procalcitonin (PCT) and C-reactive protein (CRP) levels in urinary tract infections (UTIs). A retrospective study included 314 UTI hospitalized patients divided into two groups (268 with lower UTI, 46 with upper UTI) in a tertiary care hospital. PCT and CRP were performed. Bacterial isolates were identified using standard microbiological techniques, and statistical analyses were performed to assess associations between infection localization, bacterial species, PCT, and CRP levels. Age and gender showed no significant differences between the lower and upper UTIs. Escherichia coli dominated as the leading UTI pathogen. A positive correlation (r = 0.646, P < 0.001) between PCT and CRP levels was found. The subgroup with ureteritis in the upper UTI category exhibited the highest PCT and CRP levels. PCT and CRP exhibited favorable diagnostic potential in predicting upper UTIs, with AUCs of 0.644 and 0.629, respectively. The optimal cutoff values were 0.21 ng/mL for PCT and 60.77 mg/L for CRP. Sensitivities were 69.03% and 77.99%, while specificities were 56.52% and 47.83%, respectively. E. coli emerged as the predominant bacterium in UTIs. PCT and CRP demonstrated moderate diagnostic efficacy in distinguishing between upper and lower UTIs. Notably, PCT and CRP exhibited enhanced utility in identifying ureteritis., (© 2023. Springer Nature Limited.)

To investigate the characteristics and formation mechanism of ozone (O 3 ) pollution in an industrial city, an extensive one-month field campaign focusing on O 3 and its precursors (e.g., volatile organic compounds[VOC] and nitrogen oxides[NO x ]) was conducted in Zibo City, a highly industrializd city in the North China Plain, in June 2021. The 0-D box model incorporating the latest explicit chemical mechanism (MCMv3.3.1) was applied using an observation dataset (e.g., VOC, NO x , HONO, and PAN) as model contraints to explore the optimal reduction strategy for O 3 and its precursors. The results showed that ① during high-O 3 episodes, stagnant weather conditions with high temperature and solar radiation as well as low relative humidity were observed, and oxygenated VOCs and alkenes from anthropogenic VOCs contributed the most to the total ozone formation potential and OH reactivity ( k ·OH ). ② The in-situ O 3 variation was primarily affected by local photochemical production and export process horizontal to downwind areas or vertical to the upper layer. The reduction in local emissions was essential to alleviate O 3 pollution in this region. ③ During high-O 3 episodes, high concentrations of ·OH (10×10 6 cm -3 ) and HO 2 · (14×10 8 cm -3 ) radical drove and generated a high O 3 production rate (daytime peak value reached 36×10 -9 h -1 ). The reaction pathways of HO 2 ·+NO and ·OH+NO 2 contributed the most to the in-situ gross O x photochemical production (63%) and photochemical destruction (50%), respectively. ④ Compared to those during low-O 3 episodes, the photochemical regimes during high-O 3 episodes were more inclined to be considered as the NO x -limited regime. Detailed mechanism modeling based on multiple scenarios further suggested that the synergic emission reduction strategy of NO x and VOC, while focusing on NO x emission alleviation, would be practical options for controlling local O 3 pollutions. This method could also provide policy-related guidance for the precise O 3 pollution prevention and control in other industrialized Chinese cities.

In the decade since its debut, the Mesocircuit Hypothesis (MH) has provided researchers a scaffolding for interpreting their findings by associating subcortical-cortical dysfunction with the loss and recovery of consciousness following severe brain injury. Here, we leverage new findings from human and rodent lesions, as well as chemo/optogenetic, tractography, and stimulation studies to propose the external segment of the globus pallidus (GPe) as an additional node in the MH, in hopes of increasing its explanatory power. Specifically, we discuss the anatomical and molecular mechanisms involving the GPe in sleep-wake control and propose a plausible mechanistic model explaining how the GPe can modulate cortical activity through its direct connections with the prefrontal cortex and thalamic reticular nucleus to initiate and maintain sleep. The inclusion of the GPe in the arousal circuitry has implications for understanding a range of phenomena, such as the effects of the adenosine (A2A) and dopamine (D2) receptors on sleep-wake cycles, the paradoxical effects of zolpidem in disorders of consciousness, and sleep disturbances in conditions such as Parkinson's Disease.

The significant role of traffic emissions mixed from various sources in urban air pollution has been widely recognized. However, the corresponding contributions to the roadside particle distribution are poorly understood due to the mixed impacts of various sources. Particle number concentrations of different sizes at the roadside in Nankai District of Tianjin were continuously monitored using a portable aerosol particle spectrometer during the morning rush hour (07:30-09:20) from Nov. 9, 2018 to Jan. 6, 2019. Characteristic and influencing factors of particle size distributions were discussed combined with temperature and relative humidity data, while potential sources of particles at the roadside were identified based on size distribution analysis. The results showed that the average total particle number concentrations were 502 cm -3 , and the concentrations of the accumulation mode and coarse mode were 500 cm -3 and 2 cm -3 , respectively. The distribution of number concentrations at the roadside was unimodal and primarily concentrated at 0.25-0.50 μm, with peak sizes at 0.28-0.30 μm. The same distribution trend of particle number concentration and difference in the concentration in the same segment size were observed at different periods. Vehicle activity level was the main influencing factor of road particulate matter concentration on different weekdays; the probability of the high value of road particulate matter concentration was reduced by a reasonable combination of the vehicle tail numbers. Temperature and relative humidity were both found to be positively correlated with the number concentration of particles. With the increase in temperature and relative humidity, the total and peak particle number concentration showed an overall upward trend. In addition, the peak particle size increased from 0.28-0.30 μm to 0.35-0.40 μm when relative humidity was higher than 80%. Three sources, including road dust, brake and tire wear, and the aging particles from vehicle exhaust, were identified using positive matrix factorization in this study. Road dust contributed 8.6% of the total number concentration, which mainly consisted of particles with sizes above 5.00 μm. Brake and tire wear contributed 2.8% of the total number concentration of particles with a size range of 0.80-4.00 μm. The aging particles from vehicle exhaust contributed the most (88.5%), with a peak at 0.25-0.65 μm. The sources of roadside particles were mainly related to vehicle activity, whereas temperature and relative humidity also affected the particle number size distribution.

A dominant framework for understanding loss and recovery of consciousness in the context of severe brain injury, the mesocircuit hypothesis, focuses on the role of cortico-subcortical recurrent interactions, with a strong emphasis on excitatory thalamofugal projections. According to this view, excess inhibition from the internal globus pallidus (GPi) on central thalamic nuclei is key to understanding prolonged disorders of consciousness (DOC) and their characteristic, brain-wide metabolic depression. Recent work in healthy volunteers and patients, however, suggests a previously unappreciated role for the external globus pallidus (GPe) in maintaining a state of consciousness. This view is consistent with empirical findings demonstrating the existence of "direct" (i.e., not mediated by GPi/substantia nigra pars reticulata) GPe connections with cortex and thalamus in animal models, as well as their involvement in modulating arousal and sleep, and with theoretical work underscoring the role of GABA dysfunction in prolonged DOC. Leveraging 50 healthy subjects' high angular resolution diffusion imaging (HARDI) dataset from the Human Connectome Project, which provides a more accurate representation of intravoxel water diffusion than conventional diffusion tensor imaging approaches, we ran probabilistic tractography using extensive a priori exclusion criteria to limit the influence of indirect connections in order to better characterize "direct" pallidal connections. We report the first in vivo evidence of highly probable "direct" GPe connections with prefrontal cortex (PFC) and central thalamic nuclei. Conversely, we find direct connections between the GPi and PFC to be sparse (i.e., less likely indicative of true "direct" connectivity) and restricted to the posterior border of PFC, thus reflecting an extension from the cortical motor zones (i.e., motor association areas). Consistent with GPi's preferential connections with sensorimotor cortices, the GPi appears to predominantly connect with the sensorimotor subregions of the thalamus. These findings are validated against existing animal tracer studies. These findings suggest that contemporary mechanistic models of loss and recovery of consciousness following brain injury must be updated to include the GPe and reflect the actual patterns of GPe and GPi connectivity within large-scale cortico-thalamo-cortical circuits., 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 © 2022 Zheng and Monti.)

Humans have domesticated diverse species from across the plant kingdom; however, our current understanding of plant domestication is largely founded on major cereal crops. Here, we examine the evolutionary processes and genetic basis underlying the domestication of water caltrop (Trapa spp., Lythraceae), a traditional, yet presently underutilized non-cereal crop that sustained early Chinese agriculturalists. We generated a chromosome-level genome assembly of tetraploid T. natans, and then divided the allotetraploid genome into two subgenomes. Based on resequencing data from 57 accessions, representing cultivated diploid T. natans, wild T. natans (2x and 4x) and diploid T. incisa, we showed that water caltrop was likely first domesticated in the Yangtze River Valley as early as 6300 yr BP, and experienced a second improvement c. 800 years ago. We also provided strong support for an allotetraploid origin of T. natans within the past 230 000-310 000 years. By integrating selective sweep and transcriptome profiling analyses, we identified a number of genes potentially selected and/or differentially expressed during domestication, some of which likely contributed not only to larger fruit sizes but also to a more vigorous root system, facilitating nutrient uptake, environmental stress response and underwater photosynthesis. Our results shed light on the evolutionary and domestication history of water caltrop, one of the earliest domesticated crops in China. This study has implications for genomic-assisted breeding of this presently underutilized aquatic plant, and improves our general understanding of plant domestication., (© 2021 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Malignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma., Materials and Methods: We retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab., Results: The disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs . 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases., Conclusion: The platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma., 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 © 2021 Chen, Xue, Huang, Ni, Li, Li, Yang, Hu, Zheng, An and Shi.)

Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

Background: Cotton (Gossypium spp.) is the most important world-wide fiber crop but salt stress limits cotton production in coastal and other areas. Growth regulation factors (GRFs) play regulatory roles in response to salt stress, but their roles have not been studied in cotton under salt stress., Results: We identified 19 GRF genes in G. raimondii, 18 in G. arboreum, 34 in G. hirsutum and 45 in G. barbadense, respectively. These GRF genes were phylogenetically analyzed leading to the recognition of seven GRF clades. GRF genes from diploid cottons (G. raimondii and G. arboreum) were largely retained in allopolyploid cotton, with subsequent gene expansion in G. barbadense relative to G. hirsutum. Most G. hirsutum GRF (GhGRF) genes are preferentially expressed in young and growing tissues. To explore their possible role in salt stress, we used qRT-PCR to study expression responses to NaCl treatment, showing that five GhGRF genes were down-regulated in leaves. RNA-seq experiments showed that seven GhGRF genes exhibited decreased expression in leaves under NaCl treatment, three of which (GhGRF3, GhGRF4, and GhGRF16) were identified by both RNA-seq and qRT-PCR. We also identified six and three GRF genes that exhibit decreased expression under salt stress in G. arboreum and G. barbadense, respectively. Consistent with its lack of leaf withering or yellowing under the salt treatment conditions, G. arboreum had better salt tolerance than G. hirsutum and G. barbadense. Our results suggest that GRF genes are involved in salt stress responses in Gossypium., Conclusion: In summary, we identified candidate GRF genes that were involved in salt stress responses in cotton.

Background: The number of coronavirus disease 2019 (COVID-19) cases has rapidly increased all over the world. Specific information about immunity in non-survivors with COVID-19 is scarce. This study aimed to analyse the clinical characteristics and abnormal immunity of the confirmed COVID-19 non-survivors., Methods: In this single-centered, retrospective, observational study, we enrolled 125 patients with COVID-19 who were died between January 13 and March 4, 2020 in Renmin Hospital of Wuhan University. A total of 414 randomly recruited patients with confirmed COVID-19 who were discharged from the same hospital during the same period served as control. The demographic, clinical characteristics and laboratory findings at admission, and treatment used in these patients were collected. The immunity-related risk factors associated with in-hospital death were tested by logistic regression models and Receiver Operating Characteristic (ROC) curve., Results: Non-survivors (70 years, IQR: 61.5-80) were significantly older than survivors (54 years, IQR: 37-65) (P <  0.001). 56.8% of non-survivors was male. Nearly half of the patients (44.9%) had chronic medical illness. In non-survivors, hypertension (49.6%) was the most common comorbidity, followed by diabetes (20.0%) and coronary heart disease (16.0%). The common signs and symptoms at admission of non-survivors were fever (88%), followed by cough (64.8%), dyspnea (62.4%), fatigue (62.4%) and chest tightness (58.4%). Compared with survivors, non-survivors had higher white blood cell (WBC) count (7.85 vs 5.07 × 10 9 /L), more elevated neutrophil count (6.41 vs 3.08 × 10 9 /L), smaller lymphocyte count (0.69 vs 1.20 × 10 9 /L) and lower platelet count (172 vs 211 × 10 9 /L), raised concentrations of procalcitonin (0.21 vs 0.06 ng/mL) and CRP (70.5 vs 7.2 mg/L) (P < 0.001). This was accompanied with significantly decreased levels of CD3 + T cells (277 vs 814 cells/μl), CD4 + T cells (172 vs 473 cells/μl), CD8 + T cells (84 vs 262.5 cells/μl, P < 0.001), CD19 + T cells (88 vs 141 cells/μl) and CD16 +  56 + T cells (79 vs 128.5 cells/μl) (P < 0.001). The concentrations of immunoglobulins (Ig) G (13.30 vs 11.95 g/L), IgA (2.54 vs 2.21 g/L), and IgE (71.30 vs 42.25 IU/ml) were increased, whereas the levels of complement proteins (C)3 (0.89 vs 0.99 g/L) and C4 (0.22 vs 0.24 g/L) were decreased in non-survivors when compared with survivors (all P < 0.05). The non-survivors presented lower levels of oximetry saturation (90 vs 97%) at rest and lactate (2.40 vs 1.90 mmol/L) (P < 0.001). Old age, comorbidity of malignant tumor, neutrophilia, lymphocytopenia, low CD4 + T cells, decreased C3, and low oximetry saturation were the risk factors of death in patients with confirmed COVID-19. The frequency of CD4 + T cells positively correlated with the numbers of lymphocytes (r = 0.787) and the level of oximetry saturation (r = 0.295), Whereas CD4 + T cells were negatively correlated with age (r =-0.323) and the numbers of neutrophils (r = - 0.244) (all P < 0.001)., Conclusions: Abnormal cellular immunity and humoral immunity were key features of non-survivors with COVID-19. Neutrophilia, lymphocytopenia, low CD4 + T cells, and decreased C3 were immunity-related risk factors predicting mortality of patients with COVID-19.

Objective: To compare clinical characteristics between patients with chronic obstructive pulmonary disease (COPD) and COPD -OSA overlap, and to analyze the risk factors for OSA in patients with COPD. Methods: A total of 431 patients with COPD were divided into a COPD-OSA group with AHI>15 events/h or a COPD group with AHI ≤ 15 events/h according to the results of polysomnography, and their clinical characteristics were summarized. Risk factors for OSA overlap in COPD patients were identified by univariate and multivariate logistic regression analyses. Results: There were no significant differences in gender composition, dyspnea scale (mMRC) score, the numbers of acute exacerbations and hospitalizations in the last year, prevalence of coronary heart disease, or cor pulmonale or diabetes mellitus in the two groups (all P> 0.05). Age, BMI, neck circumference, smoking index, COPD assessment test (CAT) score, the values of FEV(1) or FEV(1)%, FEV(1)/FVC ratios, and the prevalence of hypertension in the COPD-OSA group with AHI>15 events/h were significantly higher than in the COPD group with AHI ≤15 events/h, while the duration of COPD and the proportion of severe COPD were lower than the COPD group with AHI≤ 15 ( P< 0.05). The scores of Charlson Comorbidity Index, Epworth Sleepiness Scale (ESS) and Sleep Apnea Clinical Score (SACS) in the COPD-OSA group were significantly higher than in the COPD group with AHI≤ 15, with all P values<0.05. Risk factors for AHI>15 OSA coinciding in patients with COPD included BMI, neck circumference, ESS, SACS and CAT ( P< 0.05). Furthermore, BMI, ESS and CAT were independent risk factors for OSA in COPD patients ( P< 0.05). Compared with mild or moderate COPD cases, patients with severe COPD (FEV(1)%<50%) had a lower risk of having OSA (β=-0.459, OR= 0.632, 95% CI 0.401-0.997, P= 0.048). Conclusions: Compared to COPD patients with AHI ≤ 15 events/h, OSA-COPD overlap patients (AHI>15 events/h) had a worse quality of life, more daytime sleepiness and higher prevalence of hypertension. BMI, ESS and CAT were independent risk factors for AHI>15 OSA in patients with COPD. The risk of having OSA in severe COPD patients was lower than cases with mild or moderate COPD.

Background: Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC., Methods: We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC., Results: C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC., Conclusion: Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.

Objective: To investigate the clinical efficacy and the possible mechanisms of saxagliptin in the treatment of type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD)., Methods: A total of 95 T2DM and NAFLD patients were randomly divided into group A (saxagliptin group), group B (glimepiride group), and group C (glimepiride combined with polyene phosphatidylcholine group)., Results: After intervention treatment for 24 w, body mass index (BMI), waist-to-hip ratio (WHR), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), and quantitative detection of liver steatosis of study subjects were observed, the action of liver steatosis in subjects of groups A and C were significantly different from those of group B; however, there were no differences between groups A and C. The FINS, HOMA-IR, and IL-6 of subjects in group A was lower than those in groups B and C; however, there were no significant differences between the latter two groups., Conclusion: For T2DM combined with NAFLD patients, the saxagliptin treatment could not only effectively control blood glucose but also attenuate insulin resistance and inflammatory injury of the liver to improve fatty liver further.

When given a long list of items to remember, people typically prioritize the memorization of the most valuable items. Prior neuroimaging studies have found that cues denoting the presence of high value items can lead to increased activation of the mesolimbic dopaminergic reward circuit, including the nucleus accumbens (NAcc) and ventral tegmental area (VTA), which in turn results in up-regulation of medial temporal lobe encoding processes and better memory for the high value items. Value cues may also trigger the use of elaborative semantic encoding strategies which depend on interactions between frontal and temporal lobe structures. We used diffusion tensor imaging (DTI) to examine whether individual differences in anatomical connectivity within these circuits are associated with value-induced modulation of memory. DTI data were collected from 19 adults who also participated in an functional magnetic resonanceimaging (fMRI) study involving a value-directed memory task. In this task, subjects encoded words with arbitrarily assigned point values and completed free recall tests after each list, showing improved recall performance for high value items. Motivated by our prior fMRI finding of increased recruitment of left-lateralized semantic network regions during the encoding of high value words (Cohen et al., 2014), we predicted that the robustness of the white matter pathways connecting the ventrolateral prefrontal cortex (VLPFC) with the temporal lobe might be a determinant of recall performance for high value items. We found that the mean fractional anisotropy (FA) of each subject's left uncinate fasciculus (UF), a fronto-temporal fiber bundle thought to play a critical role in semantic processing, correlated with the mean number of high value, but not low value, words that subjects recalled. Given prior findings on reward-induced modulation of memory, we also used probabilistic tractography to examine the white matter pathway that links the NAcc to the VTA. We found that the number of fibers projecting from left NAcc to VTA was reliably correlated with subjects' selectivity index, a behavioral measure reflecting the degree to which recall performance was impacted by item value. Together, these findings help to elucidate the neuroanatomical pathways that support verbal memory encoding and its modulation by value.

Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n=178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n=142; RJH set, n=104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.

Objective: To evaluate the efficacy of cuffed tracheostomy tube with inner cannula for the treatment of intractable aspiration after partial laryngectomy. Methods: From May 2010 to June 2015, 15 patients with intractable aspiration after partial laryngectomy of laryngeal and hypopharyngeal carcinoma were enrolled. Cuffed tracheostomy tube with inner cannula was used in the 15 patients for treatment of intractable aspiration. The patients and their family were trained to manage the cuffed tracheostomy tube with inner cannula and to eat since the 14th day after surgery. Cuff was initially inflated with 10 ml air and then deflated of 0.5 ml air every 2-3 days. Until the inflation of cuff was no longer required, the cuffed tracheostomy tube was replaced by metal tracheostomy tube. The patients' swallowing function and aspiration were evaluated 6 months after treatment. Results: The 15 cases with intractable aspiration were treated with cuffed tracheostomy tube with inner cannula and after 2-3 months, 14 of them replaced the cuffed tracheostomy tubes with inner cannula by metal tracheostomy tubes and recovered oral eating, and tracheostomy tubes were no longer required for 12 of 14 patients in following 3-6 months, showing a total decannulation rate of 80% in the patients with refractory aspiration. Conclusion: It was safe and effective to treat aspiration after laryngeal and hypopharyngeal surgery with cuffed tracheostomy tube with inner cannula.

Solute carrier family 34 member 2 (SLC34A2), a pH-sensitive sodium-dependent phosphate transporter, is associated with several human cancers. In this study, we investigate the clinical significance of SLC34A2 and its function in human bladder cancer (BC). The expression dynamics of SLC34A2 were examined in two independent cohorts of BC samples by quantitative PCR, western blotting and immunohistochemical staining. In the training cohort (156 cases), we applied the X-tile program software to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (130 cases), the cutoff score derived from X-title analysis was investigated to determine the association of SLC34A2 expression with survival outcome. A series of in vitro and in vivo assays were then performed to elucidate the function of SLC34A2 in BC and its underlying mechanisms. Results showed that SLC34A2 was significantly upregulated in BC cell lines and clinical samples. In both two cohorts of BC samples, high expression of SLC34A2 was associated with large tumor size, advanced T status and poor patients' survival. The depletion of SLC34A2 in BC suppressed cellular viability, colony formation and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo, whereas overexpression of SLC34A2 had the converse effect. Simultaneously, downregulation of SLC34A2 decreased the transcriptional activity and protein expression level of c-Myc in BC cells, whereas restoration of c-Myc expression could compromise the anti-proliferation effect of SLC34A2 depletion. Furthermore, miR-214 was proved as a negative regulator of SLC34A2. Our present study illustrated that SLC34A2 has an important role in promoting proliferation and tumorigenicity of BC, and may represent a novel therapeutic target for this disease.

Background: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated., Methods: In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC., Results: We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients., Conclusion: Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.

Purpose: We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC., Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy., Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain- and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3β/β-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC., Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. ©2016 AACR., (©2016 American Association for Cancer Research.)

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo-cortical system. However, thalamo-cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS-, i.e., low-level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high-level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo-cortical circuits could differentiate between VS, MCS-, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole-brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo-cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar-occipital connections when compared with MCS-. Moreover, MCS- exhibited significantly less thalamo-premotor and thalamo-temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo-cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431-443, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Seasonal variations of the phytochemicals contents in needles of T. wallichiana var. mairei due to the effects of growth meteorological parameters were investigated in this study. The needles of T. wallichiana var. mairei were collected from different months and the contents of taxoids (paclitaxel, 10-deacetylbaccatin III (10-DAB), baccatin III, cephalomannine, 10-deacetyltaxol (10-DAT)), flavones (ginkgetin, amentoflavone, quercetin) and polysaccharides were quantified by ultra performance liquid chromatography (UPLC) and the resonance light scattering (RIL) method. The content of taxoids gave the highest level of 1.77 ± 0.38 mg·g -1 in January, and the lowest value of 0.61 ± 0.08 mg·g -1 in September. Unlike taxoids, the content of flavonoids was the highest in August. The content of polysaccharides reached peak value of 28.52 ± 0.57 mg·g -1 in September, which was two times higher than the lowest content of 9.39 ± 0.17 mg·g -1 in January. The contents of paclitaxel, 10-DAB, 10-DAT and polysaccharides significantly depended on meteorological parameters. The mean of minimum temperature (R = -0.61) and length of daylight (R = -0.60) were significantly correlated to 10-DAB content, while 10-DAT level showed significant correlation with length of daylight (R = -0.70) and relative humidity (R = 0.70). In addition, temperature had significantly negative effect on the content of paclitaxel and a significantly positive effect on that of polysaccharides. This study enriched the knowledge on the accumulation pattern of metabolites and could help us to determine the collecting time of T. wallichiana var. mairei for medicinal use.

Background: To determine the mechanism by which the flavonoid glycoside astragalin (AST) reduces ovarian failure in an aged rat model of menopause., Methods: The in vivo effect of AST on granulosa cell (GC) apoptosis in aged female rats was determined using flow cytometry. In vitro, the effects of AST on cultured GCs were investigated using the MTT proliferation assay and western blot assays., Results: Aged rats had significantly higher GC apoptosis as compared with young female rats. Treatment of aged rats with AST (all three doses; p < 0.01) or Progynova (p < 0.01) significantly reduced GC apoptosis as compared with the aged controls. The proportions of total apoptotic GCs was 25.70%, 86.65%, 47.04%, 27.02%, 42.09% and 56.42% in the normal, aged, 17β-estradiol (E₂), high dose AST, medium dose AST, and low dose AST-treated groups, respectively. Significant increases of serum E₂ and P₄ levels, as well as altered levels of serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels. In cultured rat GCs, AST stimulated GC proliferation, E₂ and progesterone (P₄) secretion, reduced apoptosis, reduced the level of the pro-apoptotic protein Bcl-2 (p < 0.01), but had no effect on BAX., Conclusions: AST enhanced ovarian function in aged female rats by increasing E₂ and P₄ levels, and reducing ovarian GC apoptosis via a mechanism involving Bcl-2. These data demonstrate a new pharmacological activity for AST, as well as a novel mechanism of action, and further suggest that AST may be a new therapeutic agent for the management of menopausal symptoms.

Guanine nucleotide binding protein (G protein), alpha 13 (GNA13) has been implicated as an oncogenic protein in several human cancers. In this study, GNA13 was characterized for its role in gastric cancer (GC) progression and underlying molecular mechanisms. The expression dynamics of GNA13 were examined by immunohistochemistry (IHC) in two independent cohorts of GC samples. A series of in-vivo and in-vitro assays was performed to elucidate the function of GNA13 in GC and its underlying mechanisms. In both two cohorts of GC samples, we observed that GNA13 was markedly overexpressed in GC tissues and associated closely with aggressive magnitude of GC progression and poor patients' survival. Further study showed that upregulation of GNA13 expression increased the proliferation and tumorigenicity of GC cells in vitro and in vivo, by promoting cell growth rate, colony formation, and tumor formation in nude mice. By contrast, knockdown of GNA13 effectively suppressed the proliferation and tumorigenicity of GC cells in vitro and in vivo. Our results also demonstrated that the molecular mechanisms of the effect of GNA13 in GC included promotion of G1/S cell cycle transition through upregulation of c-Myc, activation of AKT and ERK activity, suppression of FOXO1 activity, upregulation of cyclin-dependent kinase (CDK) regulator cyclin D1 and downregulation of CDK inhibitor p21Cip1 and p27Kip1. Our present study illustrated that GNA13 has an important role in promoting proliferation and tumorigenicity of GC, and may represent a novel prognostic biomarker and therapeutic target for this disease.

Plenty of studies have established that dysregulation of autophagy plays an essential role in cancer progression. The autophagy-related proteins have been reported to be closely associated with human cancer patients' prognosis. We explored the expression dynamics and prognostic value of autophagy-related protein ULK1 by immunochemistry (IHC) method in two independent cohorts of nasopharygeal carcinoma (NPC) cases. The X-tile program was applied to determine the optimal cut-off value in the training cohort. This derived cutoff value was then subjected to analysis the association of ULK1 expression with patients' clinical characteristics and survival outcome in the validation cohort and overall cases. High ULK1 expression was closely associated with aggressive clinical feature of NPC patients. Furthermore, high expression of ULK1 was observed more frequently in therapeutic resistant group than that in therapeutic effective group. Our univariate and multivariate analysis also showed that higher ULK1 expression predicted inferior disease-specific survival (DSS) (P<0.05). Consequently, a new clinicopathologic prognostic model with 3 poor prognostic factors (ie, ULK1 expression, overall clinical stage and therapeutic response) could significantly stratify risk (low, intermediate and high) for DSS in NPC patients (P<0.001). These findings provide evidence that, the examination of ULK1 expression by IHC method, could serve as an effective additional tool for predicting therapeutic response and patients' survival outcome in NPC patients.

Axon development requires membrane addition from the intracellular supply, which has been shown to be mediated by Rab10-positive plasmalemmal precursor vesicles (PPVs). However, the molecular mechanisms underlying the membrane trafficking processes of PPVs remain unclear. Here, we show that myristoylated alanine-rich C-kinase substrate (MARCKS) mediates membrane targeting of Rab10-positive PPVs, and this regulation is critical for axon development. We found that the GTP-locked active form of Rab10 binds to membrane-associated MARCKS, whose affinity depends on the phosphorylation status of the MARCKS effector domain. Either genetic silencing of MARCKS or disruption of its interaction with Rab10 inhibited axon growth of cortical neurons, impaired docking and fusion of Rab10 vesicles with the plasma membrane, and consequently caused a loss of membrane insertion of axonal receptors responsive to extracellular axon growth factors. Thus, this study has identified a novel function of MARCKS in mediating membrane targeting of PPVs during axon development.

Objectives: Enhanced external counterpulsation (EECP) could improve endothelium-dependent vasodilatation of carotid artery and restore imbalance of nitric oxide and endothein-1 in patients with coronary artery disease. Our study was designed to test the hypothesis that long-term EECP may protect vascular endothelial cells from apoptosis by modifying apoptosis-related gene expression., Methods: Eighteen male Yorkshire pigs were randomly assigned to three groups: usual diet (Normal), high cholesterol diet (HC) and high cholesterol diet plus EECP (HC+EECP). Vascular endothelial cells were isolated from the aortic endothelium and identified by CD31 staining and DiI-Ac-LDL reaction. Morphological changes were observed by both scanning and transmission electronic microscopes. TUNEL technique was applied to detect the apoptotic index of vascular endothelial cells. Two genes, Apaf-1 and BIRC2, were chosen for exploring the potential mechanisms of action at the molecular level., Results: EECP brought a certain degree of alleviation from ultrastructural changes such as shrinking and blebbing of cytomembrane, marginalization, degeneration, and fragmentation of the nucleus. EECP also significantly reduced apoptotic indices while compared with that of control (177±12‰ vs. 237±23‰, P<0.05). The Apaf-1 expression at both protein and mRNA level in pigs of HC+EECP group was significantly decreased than those of the HC group (P<0.05), whereas the BIRC2 expression was significantly enhanced after EECP treatment, documented by immunostaining and semi-quantitative RT-PCR analysis, respectively (P<0.05)., Conclusions: EECP could protect vascular endothelial cells from apoptosis, thereby delaying the progression of early atherosclerotic lesions possibly through transcriptional down-regulation of pro-apoptotic gene Apaf-1, and up-regulation of anti-apoptotic gene BIRC2., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: The purpose of this study is to investigate the relationship between the cognitive impairment and NAA/Cr and Cho/Cr ratios in the proton magnetic resonance spectroscopy ((1)HMRS), and to assess the importance of (1)HMRS in the early diagnosis of cognitive impairment in patients with ischemic white matter lesions (WMLs)., Materials and Methods: A total of 45 patients (23 males and 22 females) with the ischemic WML were divided into mild WML group (n = 15), moderate WML group (n = 15), and severe WML group (n = 15). A total of 15 healthy controls (8 males and 7 females) with no WML on magnetic resonance imaging were included. (1)HMRS focusing on the frontal lobe white matter around the anterior horn of the lateral ventricle and Montreal Cognitive Assessment (MoCA) were conducted., Results: Patients with more severe WML had lower MoCA scores. The NAA/Cr ratio in (1)HMRS was reduced in all the patients and was strongly correlated with the total MoCA scores (r = 0.845, P < 0.001). The Cho/Cr ratio in (1)HMRS was increased in mild and moderate patients, was negatively correlated with the total MoCA scores (r = 0.907, P < 0.001). The Cho/Cr ratio was reduced in the severe patients and was positively correlated with the total MoCA scores (r = 0.937, P < 0.001). In addition, NAA/Cr and Cho/Cr ratios in (1)HMRS were changed in patients with the mild WML whose total MoCA scores were similar to the controls., Conclusion: Our results suggest that NAA/Cr and Cho/Cr ratios in (1)HMRS are useful indicators for early diagnosis of ischemic WML and cognitive impairment in patients with ischemic WML.

Aim: To investigate whether XRCC1 and ADPRT polymorphisms might be associated with outcomes of breast cancer., Methods: A prospective study was conducted with a total of 335 breast cancer patients undergoing chemotherapy consecutively collected from Jan. 2005 to Jan. 2008. Genotyping of XRCC1 and ADPRT polymorphisms was conducted by PCR-RFLP assay., Results: All 335 patients were followed up until death or the end of Jan. 2012, with a median follow-up period of 38.8 (2-64) months. It was shown that the variant genotype of XRCC1 399Gln/Gln was strongly significantly associated with a decreased risk of death from breast cancer, with an HR (95% CI) of 0.52 (0.28-0.91). Similarly, individuals carrying the ADPRT 762Ala/Ala demonstrated longer survival compared to ADPRT 762 Val/ Val, with an HR (95% CI) of 0.58 (0.31-0.97). Individuals with combination genotypes of XRCC1 399Gln allele and ADPRT 762Ala/Ala presented with a longer survival, the HR (95% CI) being 0.56 (0.32-0.97)., Conclusion: We found a significant association between XRCC1399Gln/ Gln and ADPRT 762Ala/Ala polymorphisms and clinical outcomes. These two genotypes could be used as a surrogate markers of clinical outcome in glioma cases receiving chemotherapy.

Background: Enhanced external counterpulsation (EECP) improves ischemia in patients with refractory angina pectoris, but the mechanism remains unclear. To explore the mechanisms of EECP action, we detected progenitor cells presenting any of the following markers CD34(+), CD29(+), and CD106(+)., Methods: Growth cytokines-mediated progenitor cell mobilization and associated angiogenesis potential were assessed in a porcine model of hypercholesterolemia. Twenty-four male domestic swines were randomly assigned to 4 groups: normal diet (control, n = 6), hypercholesterolemic diet (CHOL, n = 6), hypercholesterolemic diet with administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) (rhG-CSF, n = 6), and hypercholesterolemic diet with EECP treatment (EECP, n = 6). EECP was applied 2 hours every other day for a total of 36 hours. Serum levels of vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor (G-CSF), peripheral blood progenitor cell counts, level of regional angiogenesis, and expression of VEGF and stromal cell derived factor 1alpha (SDF-1alpha) in porcine myocardium were assessed, respectively., Results: A porcine model of hypercholesterolemia-induced arteriosclerosis was successfully established. There was no significant difference in serum levels of VEGF among the four groups. The serum levels of G-CSF in the EECP group increased significantly at week 15 and week 18 ((38.3 +/- 5.6) pg/ml at week 15 vs (26.2 +/- 3.7) pg/ml at week 12, P < 0.05, and (46.9 +/- 6.1) pg/ml at week 18 vs (26.2 +/- 3.7) pg/ml at week 12, P < 0.01). The serum levels of G-CSF in group 3 increased also significantly after receiving rhG-CSF injection for five days ((150 +/- 13.9) pg/ml at week 18 vs (24.8 +/- 5.4) pg/ml at week 12, P < 0.01). Compared to other groups and other time points, progenitor cell counts increased significantly after 2-hour EECP treatment (108 +/- 13 vs 26 +/- 6 per 10(5) leukocytes, P < 0.01), but not at week 18. The progenitor cell counts also increased significantly after subcutaneous injection of rhG-CSF for five days compared to the week 12 (baseline) (180 +/- 21 vs 25 +/- 7 per 10(5) leukocytes, P < 0.01). There was no significant difference among the four groups at other time points. Moreover, the expression of VEGF and SDF-1alpha and the level of regional angiogenesis in myocardium increased significantly in both EECP and rhG-CSF groups., Conclusions: The results demonstrated that EECP could facilitate angiogenesis in the myocardium of atherosclerotic swines by increasing endogenous G-CSF, inducing an enhanced mobilization of progenitor cells and augmenting myocardial expression of VEGF and SDF-1alpha.

Objective: To explore the effect of long-term enhanced external counterpulsation (EECP) on morphological damage of endomembrane and endothelium-dependent vasodilatation of the carotid arteries of hypercholesterolemic pigs., Methods: Eighteen male infant pigs were randomly divided into three groups according to the contents of their diet: the normal control group (n=6), the high-cholesterol feeding control group (n=6) and EECP group (n=6). Porcine model of hypercholesterolemia was reproduced by feeding animals with high-cholesterol diet. After completion of EECP treatment for 36 hours in EECP group, carotid arterial rings were harvested from all animals. Both scanning and transmission electron microscopy was employed to observe the changes in morphology of their endomembrane. At the same time, their vasodilatation response to variant dose of acetylcholine (Ach) was detected., Results: The surface of endothelium in the normal control group was smooth, and endothelial cells were in regular streamline array, and they were almost in same size, attaching closely to matrix without smooth muscle cell proliferation and lipid infiltration in intima. In contrast, the endothelial cells of hypercholesterolemic pigs were in irregular array, with marked desquamation, resulting in loose linkage. Smooth muscle cells were found to invade into intimal layer and proliferated, and foam cells could also be found in intimal layer. In hypercholesterolemic pigs treated with EECP, slight intimal damage was found. In addition, with Ach dose of 10(-8) mol/L to 10(-5)mol/L, endothelium-dependent vasodilatation ratio in hypercholesterolemic pigs with or without EECP treatment, was significantly lower than that of the normal control group (all P<0.05). However, endothelium-dependent vasodilatation ratio in pigs with EECP treatment was obviously higher compared with hypercholesterolemic pigs without EECP treatment with the dosage of Ach concentration ranged from 10(-7) mol/L to 10(-5) mol/L (all P<0.05)., Conclusion: Long-term EECP ameliorates both the morphological damage and the impaired endothelium-dependent vasodilatation function resulting from hypercholesterolemia, contributing to prevention of atherosclerosis.

Objective: To assess the role of probiotics in the prevention of neonatal necrotizing enterocolitis (NEC) and to investigate the risk factors for NEC., Methods: A total of 2528 hospitalized neonates between January 2002 and May 2005 were assigned into either receiving prophylactic use of probiotics bifoco (Prevention group, n=1182) or without probiotics supplementation (Control group, n = 1346). The incidence of NEC was compared between the two groups. The risk factors for NEC were investigated by conditional logistic regression multifactorial analysis., Results: There were 19 cases of NEC in the Control group (1.41%), but only 6 cases in the Prevention group (0.51%) (P < 0.05). Gestational age (OR = 5.521), hypoxicdouble ended arrowischemic encephalopathy (OR = 3.887), specticemia (OR = 4.854) and critical illness scores (OR = 5.989) were the risk factors for NEC, while the prophylactic use of probiotics was an independent protective factor for NEC (OR = 0.255)., Conclusions: The prophylactic use of probiotics may reduce the incidence of NEC in neonates.

The adsorption and oxidation of 1-butanol in alkaline media on a platinum electrode were investigated mainly by EQCM and in situ FTIR spectroscopy. The experimental results demonstrate that the electrooxidation of 1-butanol is closely relative to solution acidity. Since no chemically adsorbed species, such as CO, were evidenced by in situ FTIR spectroscopy, the adsorption of 1-butanol or its dissociative products on Pt surface is suggested by EQCM and CV data. Only one current peak of 1-butanol oxidation in PGPS was detected at -0.23 V/SCE, which illustrated the disappearance of the second current peak due to Pt electrode passivation in alkaline media. The final product of 1-butanol oxidation is only butyric acid anion under experimental condition. It may therefore be suggested that the main reaction occurring at the electrode is the oxidation of 1-butanol to butyric acid anion. The EQCM studies provide quantitative results of surface mass variation and have shed light on elucidating 1-butanol oxidation.

Objective: To investigate the effects of external counterpulsation (ECP) on shear stress and signal transduction in canines with myocardial infarction., Methods: Nineteen healthy dogs were randomly divided into control, ischemia, and ischemia plus ECP groups. Myocardial infarction was induced in the latter two groups by ligation of the left anterior descending artery (LAD). Serum and aorta NO levels of the dogs were determined by modified nitrate reductase method, and serum and aorta cyclic guanosine monophosphate (cGMP) levels by radioimmunoassay., Results: The shear stress in the truncus brachiocephalicus decreased after LAD ligation, but increased significantly after 2 h of ECP treatment. Serum and aorta NO levels in ECP and control groups were significantly higher than those in the ischemic group (P<0.05). Serum and aorta cGMP levels in control group and ECP group after LAD ligation were also significantly higher than those in the ischemic group (P<0.05)., Conclusion: ECP can increase the shear stress and increase NO and cGMP levels in dogs with myocardial ischemia, which might be an important mechanism of ECP for protection of the ischemic myocardium.

Enhanced external counterpulsation (EECP) significantly augments diastolic blood flow and has been postulated to improve endothelial function by increased shear stress. We examined the effects of EECP on plasma nitric oxide and endothelin-1 (ET-1) levels. Plasma nitrate and nitrite (NOx) and ET-1 levels were measured serially in 13 patients with coronary artery disease who received 1-hour daily treatments of EECP over 6 weeks. During the course of EECP therapy, plasma NOx progressively increased and plasma ET-1 progressively decreased. After 36 hours of EECP, there was a 62 +/- 17% increase in plasma NOx compared with baseline (43.6 +/- 4.3 vs 27.1 +/- 2.6 micromol/L, p <0.0001) and a 36 +/- 8% decrease in plasma ET-1 (76.7 +/- 9.5 vs 119.5 +/- 8.5 pg/L, p <0.0001). At 3 months after completion of EECP, NOx remained 12 +/- 11% above baseline (p = 0.002), and ET-1 remained 11 +/- 10% below baseline (p = 0.0068). Our data provides neurohormonal evidence to support the hypothesis that EECP improves endothelial function.

Objective: To establish a pig model of chronic external counterpulsation., Methods: Twelve pigs were anaesthetized with sodium pentobarbital (< or =30 mg/kg.b.w.) and 846 mixture (< or =0.1 ml/kg.b.w.) and counterpulsed in a lateral position for 2 h every two days (totally 36 h) with 0.025 to 0.04 MPa/cm(2) pressure., Results: External counterpulsation was successfully completed in all the animals. Combined administration of sodium pentobarbital and 846 mixture resulted in good anesthetic effect with reduced anesthetic dosage and minimal side effect on the viscera (the liver, kidney and heart, etc)., Conclusion: The pig model of chronic external counterpulsation has been successfully established. Combined use of sodium pentobarbital and 846 mixture is recommended for chronic external counterpulsation.

Objective: To study the effects of enhanced external counterpulsation (EECP) on the vascular morphology, and endothelial function using experimentally induced hypercholesterolemic pigs., Methods: Thirty five male pigs were randomly divided into three groups: 7 normal control animals, 11 hypercholesterolemic animals, and 17 hypercholesterolemic animals receiving EECP. Serum cholesterol was measured. The coronary arteries and aortas were sampled for histopathologic and ultrastructural examination. The NF-kappaB protein expression of porcine coronary arteries was investigated by immunofluorescence., Results: Compared with the normal controls, serum cholesterol levels were significantly higher in the hypercholesterolemic animals with or without EECP. The plaque/intimal area ratio of the aorta decreased significantly in animals receiving EECP [(3.33 +/- 2.40)%, versus (12.03 +/- 7.12)% in those without EECP, P < 0.05]. Lipid deposition, endothelial damage and proliferation of smooth muscle cells were less severe in animals receiving EECP than those not. Moreover, activation and expression of NF-kappaB also decreased significantly (P < 0.05) in animals receiving EECP., Conclusions: EECP improves the morphology and function of vascular endothelium, and retards the development and progression of atherosclerosis, likely through the inhibition of NF-kappaB signaling pathway.