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Deficiency of G protein-coupled receptor kinase 2 (GRK2) was found to protect mice from dextran sulfate sodium (DSS)-induced colitis. Paeoniflorin-6'-O-benzene sulfonate (CP-25) has been shown to exert anti-inflammatory immune regulatory effects in animal models of inflammatory autoimmune disease. This study aimed to investigate the of GRK2 in the pathogenesis of ulcerative colitis (UC) and its effects on macrophage polarization, macrophage subtype regulation of intestinal barrier function, and therapeutic effects of CP-25 in mice with DSS-induced colitis. We found imbalanced macrophage polarization, intestinal barrier dysfunction, and abnormal activation of GRK2 and TLR4-NF-κB-NLRP3 inflammasome signaling pathway in the colonic mucosa of patients with UC. CP-25, restored the damaged intestinal barrier function by inhibiting the transmembrane region of GRK2 in macrophages stimulated by lipopolysaccharides. CP-25 exerted therapeutic effects by ameliorating clinical manifestation, regulating macrophage polarization, and restoring abnormally activated TLR4-NF-κB-NLRP3 inflammasome signaling pathway by inhibiting GRK2. These data suggest the pathogenesis of UC may be related to the imbalance of macrophage polarization, which leads to abnormal activation of TLR4-NF-κB-NLRP3 inflammasome signaling pathway mediated by GRK2 and destruction of the intestinal mucosal barrier. CP-25 confers therapeutic effects on colitis by inhibiting GRK2 translocation to induce the downregulation of TLR4-NF-κB-NLRP3 inflammasome signaling in macrophages.

Background NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. Methods NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. Results NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. Conclusions We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.

Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale.

Background Simple hepatic cysts are relatively common in adults, and mostly appear as asymptomatic incidental radiologic findings. Occasionally, a large cyst will cause symptoms. Elevations in the serum biomarkers protein induced by vitamin K absence (PIVKA)-II, cancer antigen (CA) 12-5, and CA19-9 are often associated with malignant tumors in the liver or bile ducts. This is the first report to describe a case of hepatic cyst with elevated levels of PIVKA-II and CA12-5. Case summary An 84-year-old Chinese woman was admitted with gradual abdominal distension. Her symptoms started 1 year ago, and she had poor appetite and a weight loss of 5 kg within the past 2 wk. She denied any symptoms associated with abdominal pain, fever and chills, nausea and vomiting, etc. The abdomen was enlarged, more in the right upper quadrant, without tenderness. Laboratory examination showed significantly increased serum levels of PIVKA-II, CA12-5, and CA19-9. A computed tomography scan revealed multiple round cysts in the liver with clear boundaries. The largest cyst was 20.1 cm × 12.2 cm × 19.6 cm in size, located in the right lobe of the liver with mild dilatation of the intrahepatic bile duct, but there was no contrast enhancement. Percutaneous drainage on the largest hepatic cyst and polycinnamol sclerosing agent injection into the cyst cavity were performed. After treatment, the patient's symptoms relieved and the elevated serum tumor makers reduced to the normal levels dramatically. Conclusion The present report identifies an unusual case of a giant hepatic cyst with marked elevation of serum tumor marker levels of PIVKA-II, CA12-5, and CA19-9. After treatment, these three serum markers dramatically decreased to normal levels. The mechanisms for the elevation of these tumor markers may be as follows: (1) A giant hepatic cyst compresses the liver, causing injury to the hepatocytes, which may lead to secretion of a large amount of PIVKA-II; and (2) Some tumor-associated antigens, such as carcinoembryonic antigen, CA19-9, CA12-5, and CA15-3, are expressed on inflammatory cells.

Contentment is an emotion that arises from the perception of completeness in life. Through a series of validation studies, the purpose of this work was to develop a scale of dispositional contentment, The Positive Emotion Assessment of Contentment Experience (PEACE) Scale. The PEACE Scale demonstrated favorable psychometric properties, including single factor structure, high internal consistency (α = .93), temporal reliability (r = .86), and construct and predictive validity. Scores on the PEACE Scale were positively correlated with all Big Five personality traits except for neuroticism. Scores also correlated positively with unconditional self-acceptance, and negatively with depression, anxiety, and stress. In addition, high levels of contentment were predictive of lower materialism and greed. Potential uses of the scale are discussed.

Background: Liver cancer is the second leading cause of worldwide cancer-related death, and it has an increasing incidence rate. To investigate the role of SRC-1 and Twist1 in liver cancer and determine their expression in terms of prognosis for patients with liver cancer and in general for hepatocellular carcinoma (HCC) cell lines. Methods: The present study included a total of 70 patients who underwent liver transplantation or hepatic resection surgeries in our hospital from May 2011 to December 2012. Demographic data and clinical variables as well as alpha-fetoprotein (AFP) and hepatitis B virus (HBV) data were collected. The expression of SRC-1 and Twist1 was determined using immunohistochemistry (IHC). The expression of SRC-1 in different HCC cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Following SRC-1 silencing by sh-RNA, cell viability, invasion, migration and expression of epithelial- mesenchymal transformation (EMT)-related proteins as well as Twist levels were measured. Results: The expression of SRC-1 and Twist1 was positively correlated in HCC patients. The expression of SRC-1 differed significantly based on patient tumor diameter, tumor-node-metastasis (TNM) grade, and state of liver cirrhosis, and it also differed in patients with dissimilar tumor metastasis conditions, while the expression of Twist1 in patients was significantly correlated with TNM grade and state of liver cirrhosis as well as by the conditions of tumor metastasis. Survival analysis showed that the expression of both SRC-1 and Twist1 were significantly associated with the overall survival (OS) time of HCC patients. Meanwhile, patients with both SRC-1 (+) and Twist1 (+) tissue had the lowest OS, while patients with both SRC-1 (–) and Twist1 (–) tissue had the highest OS. Cox univariate and multivariate analyzes showed that SRC- 1 expression, tumor stage and liver cirrhosis were independent risk factors for OS time. SRC-1 was highly expressed in HCC cell lines, and inhibition of SRC-1 had a significantly negative impact on cell viability, invasion, migration and EMT; it also inhibited the expression of Twist. Conclusions: Expression of both Twist1 and SRC-1 were correlated with clinical outcomes and prognoses for HCC patients, and both Twist1 and SRC-1 were independent risk factors for HCC patient survival conditions. Inhibition of SRC-1 suppressed cell proliferation, invasion, migration and EMT of HCC cells, which might be the result of Twist inhibition.

In many Asian cities, periodic changes in the demand for emergency medical services are concerned, but few existing studies have discussed the time-dependent factor in delivering these services. This study proposes a formula for locating emergency medical services, in which factors of varying demand, time-dependence, cost and facility capacity are considered. A real case is investigated in order to understand the impact of time-dependence on decision making. The case study suggests different solutions depending on whether the design is service-oriented or cost-oriented. The analysis also indicates that the limitations on demand complicate the making of decisions to optimise service locations, e.g., more service stations are required. By creating a design for allocating service sites based on demand nodes in a real case, this study provides a framework for analysing the location problem when demand changes.

Background The resection of small colorectal polyps (≤10 mm) is routine for endoscopists. However, the management of one of its main complications, namely delayed (within 14 days) postpolypectomy bleeding (DPPB), has not been clearly demonstrated. We aimed to assess the role of coloscopy in the management of DPPB from small colorectal polyps and identify the associated factors for initial hemostatic success. Methods We conducted a retrospective study of 69 patients who developed DPPB after the removal of colorectal polyps of ≤10 mm and underwent hemostatic colonoscopy at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between April 2013 and June 2021. Demographics, clinical variables, and colonoscopic features were collected independently. We applied univariate and multivariate analyses to assess factors associated with initial hemostatic success. Results General colonoscopy without oral bowel preparation was successfully performed in all the patients, with a median duration of 23.9 (12.5–37.9) minutes. Among 69 patients, 62 (89.9%) achieved hemostasis after initial hemostatic colonoscopy and 7 (10.1%) rebled 2.7 ± 1.1 days after initial colonoscopic hemostasis and had rebleeding successfully controlled by one additional colonoscopy. No colonoscopy-related adverse events occurred. Multivariate analysis showed that management with at least two clips was the only independent prognostic factor for initial hemostatic success (odds ratio, 0.17; 95% confidence interval, 0.03–0.91; P = 0.04). All the patients who had at least two clips placed at the initial hemostatic colonoscopy required no further hemostatic intervention. Conclusions Colonoscopy is a safe, effective, and not too time-consuming approach for the management of patients with DPPB of small colorectal polyps and management with the placement of at least two hemoclips may be beneficial.

Background Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. Methods To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. Results LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. Conclusions This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

Background The relationship between psoriasis and hepatitis C was previously controversial, so our purpose is to investigate this connection. Methods We conducted a systematic review of the case–control, cross-sectional and cohort studies examining the association between psoriasis and hepatitis C in PubMed, EMBASE and Cochrane library databases and investigated the overlapping genes between psoriasis targets and hepatitis C targets using bioinformatics analysis. Based on overlapping genes and hub nodes, we also constructed the protein–protein interaction (PPI) network and module respectively, followed by the pathway enrichment analysis. Results We included 11 publications that reported a total of 11 studies (8 cross-sectional and 3 case–control). The case–control and cross-sectional studies included 25,047 psoriasis patients and 4,091,631 controls in total. Psoriasis was associated with a significant increase of prevalent hepatitis C (OR 1.72; 95% confidence interval [CI] (1.17–2.52)). A total of 389 significant genes were common to both hepatitis C and psoriasis, which mainly involved IL6, TNF, IL10, ALB, STAT3 and CXCL8. The module and pathway enrichment analyses showed that the common genes had the potential to influence varieties of biological pathways, including the inflammatory response, cytokine activity, cytokine–cytokine receptor interaction, Toll-like receptor signaling pathway, which play an important role in the pathogenesis of hepatitis C and psoriasis. Conclusion Patients with psoriasis display increased prevalence of hepatitis C and the basic related mechanisms between hepatitis C and psoriasis had been preliminarily clarified.

Golgi-Cox staining has been used extensively in neuroscience. Despite its unique ability to identify neuronal interconnections and neural processes, its lack of consistency and time-consuming nature reduces its appeal to researchers. Here, using a spared nerve injury (SNI) mouse model and control mice, we present a modified Golgi-Cox staining protocol that can stain mouse hippocampal neurons within 8 days. In this improved procedure, the mouse brain was fixed with 4% paraformaldehyde and then stored in a modified Golgi-Cox solution at 37 ± 2°C. The impregnation period was reduced from 5–14 days to 36–48 h. Brain slices prepared in this way could be preserved long-term at –80°C for up to 8 weeks. In addition to minimizing frequently encountered problems and reducing the time required to conduct the method, our modified protocol maintained, and even improved, the quality of traditional Golgi-Cox staining as applied to hippocampal neuronal morphology in SNI mice.

Yang-Yin-Qing-Fei-Tang (YYQFT) is a well-known traditional Chinese medicine used in the treatment of chronic obstructive pulmonary emphysema, bronchitis, cytomegaloviral pneumonia, but the mechanisms of the medicine are not clear. This study aimed to identify the active components of YYQFT and elucidate the underlying mechanism on non-small cell lung cancer. First, YYQFT was extracted with different solvents, and then the most effective extract was determined by assessing their effects on non-small cell lung cancer cell growth. Second, several active compounds from YYQFT were identified, and quercetin was the one of the important active ingredients. Subsequently, the in vivo antitumor activity of quercetin was confirmed in a lung cancer xenograft model in mice. 200[Formula: see text][Formula: see text]g/mL quercetin significantly reduced tumor volume without affecting body weight of the mice. Furthermore, induction of apoptosis by quercetin was detected in tumor tissues treated with quercetin. Multiple apoptosis related genes including p53, Bax and Fas were upregulated by quercetin in tumor tissue and the ratio of Bax/Bcl-2 was increased accordingly. Our results demonstrated that quercetin, as the main effective component of the YYQFT, has potent inhibitory activity on non-small cell lung cancer by regulating the ratio of Bax/Bcl-2.

Mechanical stretch commonly promotes craniofacial suture remodeling during interceptive orthodontics. The mechanical responses of osteoblasts in craniofacial sutures play a role in suture remodeling. Moreover, the extracellular matrix (ECM) produced by osteoblasts is crucial for the transduction of mechanical signals that promote cell differentiation. Therefore, we aimed to investigate the effect of mechanical stretch on cell viability and ECM-related gene-expression changes in human osteoblasts. Human calvarial osteoblasts (HCObs) were subjected to 2% deformation. Caspase activity, MTT, and cell viability assays were used to estimate osteoblast apoptosis, proliferation, and viability, respectively. Real-time RT-PCR (RT2 -PCR) arrays were used to assess expression of cytoskeletal-, apoptosis-, osteogenesis-, and ECM-related genes. We found that mechanical stretch significantly increased osteoblast viability and cell proliferation, and decreased the activities of caspases 3 and 7. Moreover, the expression of 18 genes related to osteoblast differentiation, apoptosis, and ECM remodeling changed by more than two-fold in a time-dependent manner. Therefore, mechanical stretch promotes HCOb viability and alters expression of genes that are closely related to suture remodeling under mechanical stretch.

Intracranial aneurysms in the neonate, presenting in the first 4 weeks of life, are exceedingly rare. They appear to have characteristics, including presentation and location, that vary from those found in adults. The authors present a case of a 28-day-old neonate with a ruptured distal middle cerebral artery (MCA) aneurysm. Initial noninvasive imaging with transfontanelle ultrasound and CT confirmed intraparenchymal and subarachnoid hemorrhage. Contrast-enhanced MRI revealed a 14-mm ruptured fusiform MCA aneurysm that was not identified on time-of-flight magnetic resonance angiography (MRA). Microsurgical treatment was performed with partial neurological recovery. A comprehensive review of the literature from 1949 to 2017 revealed a total of 40 aneurysms in 37 neonates, including the present case. The most common presenting symptom was seizure. Although subarachnoid hemorrhage was the most common form of hemorrhage, 40% had intraparenchymal hemorrhage. The median aneurysm size was 10 mm (range 2–30 mm) and the most common location was the MCA, with two-thirds of cases involving the distal intracranial vasculature. Over the last 10 years, there has been a trend of increasing noninvasive diagnosis of ruptured cerebral aneurysms in neonates, with CT angiography and contrast-enhanced MRI being the most useful diagnostic modalities. The use of contrast-enhanced MRI may improve sensitivity over time-of-flight MRA. Microsurgical treatment was the most common treatment modality overall, with increased use of endovascular treatment in the last decade. Most patients underwent microsurgical vessel ligation or endovascular parent vessel occlusion. There were high rates of neurological recovery after microsurgical or endovascular treatment, particularly for patients with distal aneurysms.

BACKGROUND: Defecation disorders after ileostomy reversal are among the most common complications for rectal cancer patients, and significantly diminish their quality of life. The aim of this study was to identify the risk factors associated with frequent defecation early after ileostomy reversal for rectal cancer patients. METHODS: We retrospectively collected the data of rectal cancer patients who underwent ileostomy reversal from January 2018 to December 2019 at the Sixth Affiliated Hospital of Sun Yat-sen University. We divided patients into two groups: a no frequent defecation group (≤7 times/day) and a frequent defecation group (>7 times/day). RESULTS: Of the 264 included patients, 59 patients (22.35%) had frequent defecation within 1 month after ileostomy closure and were defined as the frequent defecation group. There were no significant differences between the two groups in terms of gender, age, hypertension, and diabetes. Univariate and multivariate analyses showed that proctitis (P=0.04) and anastomotic stenosis (P=0.02) were independent risk factors for frequent defecation. Four factors, including proctitis, anastomotic stenosis, hypertension, and age were included to construct the nomogram. The consistency index of the nomogram was 0.949 and the area under the curve value was 0.623. CONCLUSIONS: For rectal cancer patients, proctitis and anastomotic stenosis were correlated with frequent defecation within 1 month after ileostomy closure. Surgeons should pay attention to the rectal examination before ileostomy reversal surgery.

The cooling effect is better than conventional cooling channels because the conformal cooling channels have a uniform distance between the mold surfaces and the channels. In this study, a new method aiming to enhance cooling efficiency in the low-pressure wax injection molding process was proposed. It was found that a reduction in cooling time of about 81% can be obtained when a wax injection mold with conformal cooling channels is compared to that without cooling channels. In addition, a rapid tooling fabricated by this technology has some distinct advantages such as rapid tooling size, interior quality of conformal cooling channels, production costs, and post-processing operations compared to the selective laser sintering technology, selective laser melting technology, and diffusion bonding technology.

Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice. In another mouse model of atherosclerosis, MRKO/APOEKO mice and floxed control/APOEKO mice were generated and treated with angiotensin II. Similarly, MRKO inhibited the atherosclerotic lesion area in APOEKO mice. Histological analysis showed that MRKO increased collagen coverage and decreased necrosis and macrophage accumulation in the lesions. In vitro results demonstrated that MRKO suppressed macrophage foam cell formation and up-regulated the expression of genes involved in cholesterol efflux. Furthermore, MRKO decreased accumulation of apoptotic cells and increased effective efferocytosis in atherosclerotic lesions. In vitro study further revealed that MRKO increased the phagocytic index of macrophages without affecting their apoptosis. In conclusion, MRKO reduces high cholesterol- or angiotensin II-induced atherosclerosis and favorably changes plaque composition, likely improving plaque stability. Mechanistically, MR deficiency suppresses macrophage foam cell formation and up-regulates expression of genes related to cholesterol efflux, as well as increases effective efferocytosis and phagocytic capacity of macrophages.

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r (2) = 0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Background: Fucoidan is a fucose-enriched, sulfated polysaccharide found in brown algae; in recent years, this polysaccharide has been found to exert several biological effects, including antitumor effects, such as antiproliferation, activating apoptosis, and anti-angiogenesis of cancer cells. However, the antimetastatic effect of fucoidan and the related targeting receptors remain unknown. In the present study, we examined the inhibition of invadopodia formation and underlying mechanism of fucoidan on human liver cancer cells. Methods: We used 98% purified fucoidan from Sargassum species to treat the hepatocellular carcinoma (HCC) cells SMMC-7721, Huh7 and HCCLM3 in vitro and the HCCLM3 cell line in vivo. The HCC cells were cultured with various concentrations of Fucoidan-Sargassum (0-30 mg/mL). Migration, invasion and wound healing assays were performed to determine the antimetastatic effect of fucoidan on the HCC cells. Western blot analysis and immunofluorescence staining were conducted to determine the expression levels of invadopodia formation-regulating proteins and the targeting membrane receptor proteins. Results: Fucoidan-Sargassum inhibited the migration and invasion of HCC SMMC-7721, Huh7 and HCCLM3 cells in a dose-dependent manner. In the HCCLM3 cells, Fucoidan-Sargassum also decreased the expression levels of invadopodia-related proteins including Src, Cortactin, N-WASP, ARP3, CDC42, MMP2, MT1-MMP, and the targeting receptors integrin αV and β3 in a dose-dependent manner. Fucoidan-Sargassum also increased the levels of endoplasmic reticulum-related proteins, including GRP78, IRE1, SPARC, and the type IV collagen receptor proteins integrin α1 and β1. In vivo, Fucoidan-Sargassum reduced the size of liver tumors and decreased the number of lung metastatic foci in nude mice with hepatocellular carcinoma xenografts. Conclusion: These findings indicate that Fucoidan-Sargassum has an antimetastatic effect on SMMC-7721, Huh7 and HCCLM3 liver cancer cells, and the underlying mechanism involves targeting ITGαVβ3 and mediating the ITGαVβ3/SRC/E2F1 signaling pathway. These results suggest that Fucoidan-Sargassum may be a promising therapeutic antimetastatic compound in the development of a metastasis-preventive drug for treating liver cancer.

Background: Pancreatic cancer risk is increased in patients with type 2 diabetes, while being reduced by metformin treatment. However, it is unclear whether metformin could be associated with clinical outcomes of patients with pancreatic cancer and concurrent type 2 diabetes. Materials and Methods: A pooled analysis of 4 publications including 1,429 patients was performed to investigate the association of metformin and overall survival(OS) in patients with pancreatic cancer and concurrent type 2 diabetes. Results: A borderline significant relative survival benefit was found in metformin treated patients compared with non-metformin treated patients (hazard ratio 0.80; 95% CI: 0.62-1.03). Conclusions: These results suggest that further investigation is warranted of whether metformin may benefit the survival of patients with pancreatic cancer and concurrent type 2 diabetes.

Previous studies have suggested that metformin may improve the survival rate of patients with pancreatic cancer (PC) by regulating the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin specifically targets mTOR. In the present study, the efficacy of metformin and rapamycin in isolation and combination were investigated for the treatment of PC. The efficacy of metformin and rapamycin in reducing the proliferation of PC cell line SW1990 in vitro and in vivo was evaluated. It was revealed that metformin (10 mmol/l) + rapamycin (2 ng/ml), metformin (15 mmol/l) + rapamycin (20 ng/ml) and metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly inhibited the viability of PC cells compared with untreated cells. Additionally, metformin (20 mmol/l) + rapamycin (200 ng/ml) significantly suppressed the expression of phosphorylated mTOR compared with metformin or rapamycin alone. Using a xenograft tumor model, it was revealed that combination treatment significantly inhibited the growth of PC cells compared with monotherapy. The present study revealed that a combination of metformin and rapamycin synergistically inhibited the growth of PC in vitro and in vivo and may be a potential treatment option for patients with PC.

In this study, we propose to use gas-filled microbubbles (MBs) simultaneously actuated by the acoustic wave to enhance the imaging contrast of optical coherence tomography (OCT)-based angiography. In the phantom experiments, MBs can result in stronger backscattered intensity, enabling to enhance the contrast of OCT intensity image. Moreover, simultaneous application of low-intensity acoustic wave enables to temporally induce local vibration of particles and MBs in the vessels, resulting in time-variant OCT intensity which can be used for enhancing the contrast of OCT intensitybased angiography. Additionally, different acoustic modes and different acoustic powers to actuate MBs are performed and compared to investigate the feasibility of contrast enhancement. Finally, animal experiments are performed. The findings suggest that acoustic-actuated MBs can effectively enhance the imaging contrast of OCT-based angiography and the imaging depth of OCT angiography is also extended.

Reactive oxygen species (ROS) appear in universal stress pathways and damage cell components. In this study, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL), a redox-cycling nitroxide and membrane-permeable antioxidant, was investigated for its ability to clear out intracellular ROS induced by hydrogen peroxide (H2O2) shock in Saccharomyces cerevisiae. Cell growth was improved by TEMPOL addition. The mechanism of ROS removal was elucidated by investigating activities of related genes, enzyme, and cofactors. TEMPOL increased the expression of genes involved in oxidative stress response, and enhanced the activities of the superoxide dismutase (SOD) and catalase (CAT) antioxidative proteins. TEMPOL also increased intracellular glutathione (GSH) to remove ROS by supplying more NADPH in cells. Finally, TEMPOL might catalyze the reaction of NADH and ROS due to its dual redox states. Interestingly, the early addition of TEMPOL resulted in a better H2O2 tolerance, because TEMPOL required time to expand its benefits in different metabolic levels for constructing an enzymatic antioxidant defense system and accumulating non-enzymatic reducing power in advance, akin to a “preventive stimulator”.

Optical coherence tomography (OCT) angiography requires high sensitivity and image penetration for detailed microvascular monitoring. Unfortunately, no effective contrast-medium-enhanced scheme is currently available for imaging improvement. We here propose the simultaneous use of gas-filled microbubbles (MBs) and acoustic actuation to enhance the imaging contrast of OCT angiography. OCT-synchronized acoustic actuation was applied in the presence of MBs, and different moving object tracking angiographic algorithms were tested in in vitro tubing and in vivo mouse experiments. This scheme significantly enhanced the OCT angiography performance, including its sensitivity and penetration, and should advance the utilization of OCT as an effective microvascular diagnostic tool.

// Jia-Wei Zhang 1,* , Lei Huang 1,2,* and A-Man Xu 1,3 1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China 2 German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China * These authors have contributed equally to this work Correspondence to: A-Man Xu, email: // Lei Huang, email: // Keywords : adenocarcinoma of esophagogastric junction, monocyte-lymphocyte ratio, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, cancer-specific survival Received : November 21, 2016 Accepted : February 07, 2017 Published : February 18, 2017 Abstract Aims: To propectively reveal the clinicopathological and prognostic significances of monocyte-lymphocyte ratio (MLR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in resected patients with non-metastatic Siewert type II/III adenocarcinoma of esophagogastric junction (AEG). Methods: A total of 611 patients diagnosed with Siewert type II/III AEG and undergoing surgery between 2006 and 2011 were prospectively followed-up until April 2016. Associations between preoperative peripheral MLR, NLR, and PLR and clinicopathological parameters were quantified using the multivariate Logistic regression model with adjustment. The correlation between the 3 ratios and cancer-specific survival (CSS) was investigated using the univariate and adjusted multivariate Cox regression models with stratifications. The periodical survival rates for the low- and high-level arms were obtained using the Kaplan-Meier method. Results: We set the medians (0.223, 2.22, and 124.4) as the cut-off values of preoperative MLR, NLR, and PLR, respectively. MLR was higher in male patients and those > 63 years; PLR was higher in patients with type II tumors. The (marginally-)significantly inverse ratio-CSS association was detected in male patients, those ≤ 63 years, those with type III tumors, and those with pTNM stage III tumors for MLR, and in female patients, those > 63 years, those with type III tumors, those with vessel invasion, and those with stage III tumors for NLR, but was generally negative concerning PLR. The association majorly existed in type III and pTNM stage III tumors. Conclusion: MLR and NLR might be prognostic factors for patients with non-metastatic Siewert type II/III AEG, while PLR had limited significance.

Purpose Lamotrigine (LTG) is a broad-spectrum antiepileptic drug that is widely used in clinic. However, the effect of LTG on cognition and neurodegeneration during epilepsy treatment remains controversial. In this study, we compared the cognitive effects of LTG and sodium valproate in pentylenetetrazole (PTZ)-kindled animal model, and the dose dependency was tested for LTG. Methods PTZ-kindled animals were divided into the following treatment groups: control group, treated with 3.5 mL/kg of 0.9% sodium chloride; low-dose LTG group, treated with 12.5 mg/kg of LTG; middle-dose LTG group, treated with 25 mg/kg of LTG; high-dose LTG group, treated with 50 mg/kg of LTG; VPA group, treated with 300 mg/kg of VPA. The Morris Water Maze (MWM) test commenced from the 10th day of treatment. Hippocampal cell apoptosis was determined by TUNEL staining after two weeks of treatment. Results Compared to the vehicle-treated control group, escape latency was significantly reduced in the middle- and high-dose LTG- and VPA-treated groups on the 3rd and 4th day of the MWM test (p

Based on nonlinear elastic theory and Hamilton’s principle, a generalized element stiffness matrix, which incorporates the effects of flexural as well as axial stresses induced by initial load, is given. A finite element method for dynamic analysis considering the effect of initial load is presented, with corresponding computer programs produced to facilitate the analysis. The formula is validated through a comparison in results with the analytical solution. The effects of key physical factors, including the type and magnitude of initial load, and stiffness parameters such as sectional inertia moment, inertia radius and span, on the dynamic characteristics of the beams with various restraint conditions are discussed with the effect of initial flexural stress considered. The results suggest that the natural frequency of the beam would be enhanced due to the existence of flexural stress induced by initial load and such as effect relates to the magnitude of initial load and stiffness parameters of the beam.

This study investigates therapeutic efficacy of photothermal therapy (PTT) in an orthotropic xenograft model of bone metastasis of breast cancer. The near-infrared (NIR) irradiation on Multi-Walled Carbon Nanotubes (MWNTs) resulted in a rapid heat generation which increased with the MWNTs concentration up to 100 μg/ml. MWNTs alone exhibited no toxicity, but inclusion of MWNTs dramatically decreased cell viability when combined with laser irradiation. Thermographic observation revealed that treatment with 10 μg MWNTs followed by NIR laser irradiation resulted in a rapid increase in temperature up to 73.4±11.98 °C in an intraosseous model of bone metastasis of breast cancer. In addition, MWNTs plus NIR laser irradiation caused a remarkably greater suppression of tumor growth compared with treatment with either MWNTs injection or NIR irradiation alone, significantly reducing the amount of tumor-induced bone destruction. All these demonstrate the efficacy of PTT with MWNTs for bone metastasis of breast cancer.

Focused ultrasound (FUS) in combination with microbubbles temporally and locally increases the permeability of the blood-brain barrier (BBB) for facilitating drug delivery. However, the temporary effects of FUS on the brain microstructure and microcirculation need to be addressed. We used label-free optical coherence tomography (OCT) and OCT angiography (OCTA) to investigate the morphological and microcirculation changes in mouse brains due to FUS exposure at different power levels. Additionally, the recovery progress of the induced effects was studied. The results show that FUS exposure causes cerebral vessel dilation and can be identified and quantitatively analyzed via OCT/OCTA. Micro-hemorrhages can be detected when an excessive FUS exposure power is applied, causing the degradation of OCTA signal owing to strong scattering by leaked red blood cells (RBCs) and weaker backscattered intensity from RBCs in vessels. The vessel dilation effect due to FUS exposure was found to abate in several hours. This study demonstrates that the FUS-induced cerebral transiently dilated effects can be in-vivo differentiated and monitored with OCTA, and shows the feasibility of using OCT/OCTA as a novel tool for long-time monitoring of cerebral vascular dynamics during FUS-BBB opening process.

BACKGROUND/AIMS Tumors generally progress due to disruption in the balance between cellular proliferation and apoptosis. Thus, regulators of these processes tend to have altered expression in tumors, making them useful diagnostic and prognostic markers in the clinic. Here, we explored the potential usefulness of proteins involved in each of these processes, Smac (apoptosis) and Ki-67 (proliferation), in pancreatic cancer. METHODOLOGY We collected 35 pancreatic cancer samples and 12 normal pancreas samples and applied immunohistochemistry and pathology to determine the expression of these two proteins and their correlation with clinicopathology of the tumors. RESULTS Both Smac (35/35) and Ki-67 (33/35) were significantly more highly expressed in pancreatic tumors than in normal pancreas (1/12 and 2/12, respectively; p

This article is to summarize the molecular and functional analysis of the gene "suppression of tumorigenicity 13" (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone) of the 70-kDa heat shock proteins (Hsc/Hsp70). By collaborating with other positive co-factors such as Hsp40 and the Hsp70-Hsp90 organizing protein (Hop), or competing with negative co-factors such as Bcl2-associated athanogen 1 (Bag1), Hip facilitates may facilitate the chaperone function of Hsc/Hsp70 in protein folding and repair, and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. Although the nomenclature of ST13 implies a role in the suppression of tumorigenicity (ST), to date available experimental data are not sufficient to support its role in cancer development, except for the possible down-regulation of ST13 in gastric and colorectal cancers. Further investigation of this gene at the physiological level would benefit our understanding of diseases such as endocrinological disorders, cancer, and neurodegeneration commonly associated with protein misfolding.