The combination of soluble tumor necrosis factor receptor type 1 and fibroblast growth factor 21 exhibits better prediction of renal outcomes in patients with type 2 diabetes mellitus.

PURPOSE: Numerous biomarkers of diabetic kidney disease (DKD) are associated with renal prognosis but head-to-head comparisons are lacking. This study aimed to examine the association of soluble tumor necrosis factor receptor type 1 (sTNFR1), fibroblast growth factor 21 (FGF-21), endocan, N-terminal pro-brain natriuretic peptide (NT-pro-BNP), and renal outcomes of patients with or without clinical signs of DKD. METHODS: A total of 312 patients were enrolled in a prospective observational study that excluded individuals with estimated glomerular filtration rates (eGFR) < 30 mL/min/1.73 m2. Composite renal outcomes included either a > 30% decline in eGFR and worsening albuminuria or both from consecutive tests of blood/urine during a 3.5-year follow-up period. RESULTS: Higher sTNFR1 and FGF-21, rather than endocan and NT-pro-BNP, levels were associated with renal outcomes but the significance was lost after adjusting for confounders. However, sTNFR1 levels ≥ 9.79 pg/dL or FGF-21 levels ≥ 1.40 pg/dL were associated with renal outcomes after adjusting for the confounders (hazard ration [HR] 2.76, 95% confidence interval [CI] 1.36-5.60, p = 0.005 for sTNFR1 level; HR 1.95, 95% CI 1.03-3.69, p = 0.03 for FGF-21 level). The combination of both levels exhibited even better association with renal outcomes than did either one alone (adjusted HR 4.45, 95% CI 1.86-10.65, p = 0.001). The results were consistent among patients with preserved renal function and normoalbuminuria. CONCLUSION: Both sTNFR1 and FGF-21 levels were associated with renal outcomes of in patients with type 2 diabetes, and the combination of the abovementioned markers exhibits better predictability.

MRI findings for diagnosis of postoperative foreign body granulomas versus recurrent tumours in patients of brain tumour surgery.

AIM: To evaluate the postoperative magnetic resonance imaging (MRI) findings of intracranial foreign body granulomas (FBGs) and true recurrent tumours (RTs) and thus lead to a basis for management decision-making. MATERIALS AND METHODS: Twenty-two patients with previous brain tumour surgery were diagnosed clinically with RT and underwent surgery. Re-operative pathology revealed FBG in eight patients and RT in 14 patients. MRI findings before the initial operation were compared to those before the re-operation. RESULTS: Features of FBGs versus RTs on MRI were as follows: (1) mean lesion size: 1.3 ± 0.7 (0.5-2.6) versus 3.2 ± 1.7 (1.1-6.3) cm (p=0.001, odds ratio [OR] = 4.18); (2) hypointensity on T2-weighted imaging (WI): 6/8 (75%) versus 0/14 (0%; p<0.001, OR=75.4); (3) non-restricted diffusion on diffusion-WI (DWI): 6/8 (75%) versus 2/14 (14.3%; p=0.008, OR=18); and (4) "ring and bubble" appearance on contrast-enhanced T1WI: 7/8 (87.5%) versus 2/14 (14.3%; p=0.001, OR=42). In comparison with their original tumours, the FBGs in the FBG group showed significantly lower T2 signal intensity, lower signal on DWI, and more cases of non-restricted diffusion on DWI (p=0.04, 0.04, 0.04, respectively). CONCLUSION: On brain MRI, FBGs can be differentiated from RTs by their relatively smaller size, hypointensity on T2WI, lack of restricted diffusion on DWI, and "ring and bubble" appearance on contrast-enhanced T1WI. Comparing the MRI findings of the focal lesion in the tumour bed with those of the original tumour is suggested to enhance diagnostic confidence.

Peripheral ProBDNF Delivered by an AAV Vector to the Muscle Triggers Depression-Like Behaviours in Mice.

Major depression is a leading cause of morbidity and disease burden in modern society. Current drug treatment is only effective in a fraction of patients as underlying mechanisms of depression are not fully understood. ProBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and its receptor p75NTR are highly upregulated in patients with major depression and in animal models of depression induced by chronic stress. Here, we hypothesise that proBDNF may be a pathogenic factor triggering depression. C57BL/6 mice were injected in the bilateral gluteus maximus muscle with AAV-proBDNF or AAV-EGFP. Four weeks after the injection, AAV-proBDNF injected animals developed depression-like behaviours, which were evident for 4-8 weeks and then returned to the control level after 12 weeks. In the second experiment, mice were divided into three groups; one group was treated with sheep anti-proBDNF antibody after AAV-proBDNF injection whereas the other two groups received PBS injection after the AAV-proBDNF or AAV-EGFP delivery. The group that was injected with AAV-proBDNF showed a time-dependent increase in immobility time in the tail suspension test and forced swim test, reduced sucrose consumption and decreased grooming time after sucrose spraying. Treatment with sheep anti-proBDNF antibody alleviated the depressive-like symptoms. Peripheral AAV-proBDNF delivery also resulted in a reduction of density and length of dendritic spines in the dentate gyrus and amygdala. Thus, we conclude that peripheral proBDNF is a primary pathogenic factor triggering depression-like behavioural changes in mice likely by reducing dendritic spine plasticity.

MiR-92b inhibits proliferation and invasion of lung cancer by targeting EZH2.

OBJECTIVE: To verify that miR-92b inhibits proliferation and invasion of lung cancer by targeting EZH2. MATERIALS AND METHODS: The expression levels of miR-92b and EZH2 in human bronchial epithelial cell line BEAS-2B and human lung cancer cell line (A549, NCI-H23, NCI-H358, NCI-H1975, PC-9) were detected, and miR-92b mimic, sh-EZH2 expression vector, and plasmid blank vector (blank group) were constructed. Blank group, miR-92b mimic, miR-92b mimic+sh-EZH2 group (combined group) were set up, MTT and transwell were used to detect the proliferation and invasion ability of A549 and NCI-H23 cells, and fluorescein report verified the regulatory relationship of miR-92b to EZH2. RESULTS: The expression level of miR-92b in A549, NCI-H23, NCI-H358, NCI-H1975, and PC-9 cells was lower than that in BEAS-2B cells (p<0.05). The expression level of EZH2 was higher than that of BEAS-2B cells (p<0.05). A549 and NCI-H23 cells were selected for transfection. After that, the expression level of miR-92 in miR-92b mimic, combined group A549 and NCI-H23 cells was higher than that in blank group (p<0.05), and miR-92b mimic had no difference with joint group (p>0.05). The expression level of EZH2 in cells of miR-92b mimic, blank group A549, and NCI-H23 was lower than that of combined group (p<0.05), and miR-92b mimic was lower than that of blank group (p<0.05). After the overexpression of miR-92b, pmirGLO-EZH2-3'UT Wt luciferase activity decreased significantly (p<0.05) but had no effect on pmirGLO-EZH2-3'UTR Mut Luciferase activity (p>0.05). Cell proliferation ability and invasion ability of A549 cells and NCI-H23 cells in miR-92b mimic group were lower than those in blank group (p<0.05), while those in combined group were higher than those in miR-92b mimic group (p<0.05). CONCLUSIONS: MiR-92b inhibits proliferation and invasion of lung cancer cells through targeted inhibition of EZH2, which is a potential target for future treatment of lung cancer.

The Long-Term Effects of Ethanol and Corticosterone on the Mood-Related Behaviours and the Balance Between Mature BDNF and proBDNF in Mice.

In this study, we aimed to establish the effects of chronic corticosterone (CORT) and ethanol administration on mood-related behaviour and the levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor protein proBDNF in mice. C57BL6 male and female mice received drinking water (n = 22), 1% ethanol in drinking water (n = 16) or 100 µg/ml corticosterone in drinking water (containing 1% ethanol, n = 18) for 4.5 weeks. At the end of experimental protocol, the open field test (OFT) and elevated plus maze test were performed. Brain and adrenal tissues were collected and mBDNF and proBDNF were measured by ELISA assays. We found that the mice fed with corticosterone and ethanol developed anxiety-like behaviours as evidenced by reduced time in the central zone in the OFT compared with the control group. Both proBDNF and mBDNF were significantly decreased in the corticosterone and ethanol groups compared with the control group in the prefrontal cortex, hippocampus, hypothalamus and adrenal. The ratio of proBDNF/mBDNF in prefrontal cortex in the corticosterone group was increased compared with the ethanol group. Our data suggest that the ratio of proBDNF/mBDNF is differentially regulated in different tissues. Ethanol and corticosterone downregulate both mBDNF and proBDNF and alter the balance of proBDNF/mBDNF in some tissues. In conclusion, the ethanol and corticosterone may cause abnormal regulation of mBDNF and proBDNF which may lead to mood disorders.

[Application of closed negative pressure irrigation and suction device in the treatment of high perianal abscess].

Objective: To explore the efficacy of closed negative pressure irrigation and suction device (Patent number: Z200780013509.8) in the treatment of high perianal abscess. Methods: From January 2015 to December 2016, ≥18-year-old patients with primary high perianal abscess who were treated at our department were prospectively enrolled. Exclusion criteria: (1) recurrent perianal abscess; (2) complicated with anal fistula formation; (3) preoperative, intraoperative or postoperative physical therapy, and curettage treatment, negative pressure irrigation; (4) Crohn's disease-related perianal abscess; (5) with immunosuppressive status, such as transplant recipients; (6) co-existence of malignant tumors, such as leukemia; (7) with diabetes; (8) those who could not receive long-term follow-up and were not suitable to participate in this study. According to the random number table method, the patients were randomly divided into negative pressure irrigation and suction group and routine drainage group. All patients were clearly diagnosed and the location and size of the perianal abscess were marked before surgery. These two groups were treated as follows: (1) Negative pressure irrigation and suction group: the skin was incised at a diameter of 1-2 cm at the site where the abscess fluctuated most obviously. After the abscess was removed, a closed negative pressure irrigation and suction device was installed and the pressure of -200 to -100 mmHg (1 mmHg=0.133 kPa) was maintained to keep the abscess cavity collapsed. Generally, the irrigation was stopped 5 days later or when the drainage was clear. The closed vacuum suction was maintained for 2 additional days, before the wound was sutured. (2) Conventional drainage group: conventional incision and drainage was carried out. The skin was cut at a diameter of 8 to 10 cm at the site of abscess with most obvious fluctuation. After the abscess was removed, normal saline gauze was used for dressing. Dressing was changed regularly until the wound healed. The efficacy, operative time, intraoperative bleeding, incision length, frequency of dressing change, pain index (visual analogue score, VAS score), postoperative healing time, complications, recurrence rate of perianal abscess, anal fistula formation rate were observed. The t test and χ2 test were used for comparison between the 2 groups. Results: There were both 40 patients in the negative pressure irrigation and suction group and the conventional drainage group. There were 28 males and 12 females in negative pressure irrigation and suction group with a mean age of (38.3±12.0) years and mean disease course of (6.6±2.1) days. The abscess in pelvic-rectal space accounted for 50.0% (20/40) and the mean diameter of abscess was (8.0±3.7) cm. There were 26 males and 14 females in the conventional drainage group with a mean age of (37.1±11.8) years and mean disease course of (6.4±2.5) days. The abscess in pelvic-rectal space accounted for 55.0% (22/40) and the diameter of abscess was (8.2±3.5) cm. The differences in baseline data between two groups were not statistically significant (all P>0.05). Both groups successfully completed the operation. There was no significant difference in operative time between two groups (P>0.05). As compared to conventional drainage group, intraoperative blood loss in negative pressure irrigation and suction group was less [(12.1±5.5) ml vs. (18.3±4.4) ml, t=5.606, P<0.001], incision length was shorter [(2.3±0.8) cm vs. (7.6±1.7) cm, t=17.741, P<0.001], postoperative VAS pain scores at 1-, 3-, 7-, and 14-day after operation were lower [3.7±1.4 vs. 7.6±1.8, t=10.816, P<0.001; 3.0±1.3 vs. 6.8±1.6, t=11.657, P<0.001; 2.7±0.9 vs. 5.1±1.1, t=10.679, P<0.001; 1.2±0.3 vs. 1.6±0.4, t=5.060, P=0.019], the dressing change within 7 days after operation was less (3.5±1.2 vs. 12.6±2.7, t=19.478, P<0.001), postoperative healing time was shorter [(10.4±3.0) d vs. (13.5±3.8) d, t=4.049, P<0.001] and postoperative complication rate was lower [17.5% (7/40) vs. 2.5% (1/40), χ2=5.000, P=0.025]. During follow-up of 12 to 36 (24±5) months, the recurrence rate of perianal abscess within 1 year after operation and anal fistula formation rate in negative pressure irrigation and suction group were lower than those in conventional drainage group [5.0% (2/40) vs. 20.0% (8/40), χ2=4.114, P=0.042 and 2.5% (1/40) vs. 17.5% (7/40), χ2=5.000, P=0.025, respectirely]. The one-time cure rate of negative pressure irrigation and suction group and conventional drainage group was 92.5% (37/40) and 62.5%(25/40), respectirely (χ2=10.323, P=0.001). Conclusions: The application of the negative pressure irrigation and suction device in the treatment of high perianal abscess can improve the efficiency of one-time cure, reduce postoperative pain, accelerate healing time, decrease the morbidity of postoperative complication and the rates of abscess recurrence and anal fistula formation, indicating an improvement of the treatment.

Gender difference in clinical and genetic characteristics of Brugada syndrome: SADS-TW BrS registry.

BACKGROUND: Brugada syndrome (BrS) is a heritable sudden cardiac death (SCD) disease with male predominance. Information on gender difference of BrS remains scarce. AIM: To investigate the gender difference of BrS in Han Chinese. DESIGN: We consecutively enrolled 169 BrS patients (153 males and 16 females) from Han Chinese in Taiwan from 1998 to 2017. METHODS: Clinical characteristics, electrocardiographic parameters and SCN5A mutation status were compared between genders. RESULTS: The percentage of family history of SCD in females was slightly higher (31.3% vs. 15%, P = 0.15). Females exhibited longer QTc (457.8 ± 33.0 vs. 429.5 ± 42.1 ms, P < 0.01). Regarding cumulative event occurrence by age, Mantel-Cox test showed females had earlier age of onset of first cardiac events (SCD or syncope) than males (P = 0.049), which was mainly attributed to syncope (P < 0.01). Males with SCD exhibited longer QRS duration (114.2 ± 26.8 vs. 104.8 ± 15.3 ms, P = 0.02) and QTc (442.5 ± 57.4 vs. 422.9 ± 28.8 ms, P = 0.02). Males with syncope exhibited longer PR interval (181.2 ± 33.7 vs. 165.7 ± 27.1 ms, P = 0.01), whereas females with SCD or syncope had a trend towards slower heart rates (69.1 ± 9.6 vs. 82.2 ± 16.3 bpm, P = 0.10) than female with no or mild symptoms. There was no difference in the percentage of SCN5A mutation between genders. CONCLUSION: Gender difference is present in BrS. Females have longer QTc and suffer from syncope earlier than males. Risk of SCD in males is associated with boarder QRS complex and longer QTc, whereas risk of syncope is associated with longer PR interval in males and slower heart rate in females.

HOXA11-AS regulates diabetic arteriosclerosis-related inflammation via PI3K/AKT pathway.

OBJECTIVE: This study aims to explore whether homeobox A11 antisense RNA (HOXA11-AS) could regulate inflammation induced by diabetic arteriosclerosis (DAA) via PI3K/AKT pathway. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect expressions of HOXA11-AS and proinflammatory genes in carotid endarterectomy samples of symptomatic and asymptomatic atherosclerosis (AS) patients, diabetes mellitus (DM), and non-DM patients. The above-mentioned genes in DM animal model and non-DM animal model were also detected. We detected the expression of HOXA11-AS in vascular smooth muscle cells (VSMCs) treated with platelet-derived growth factor (PDGF) or PDGF inhibitor imatinib, respectively. Subsequently, we applied cell transfection technology to interfere with the expression of HOXA11-AS in VSMCs. In vascular endothelial cells (VECs) and VSMCs, we detected the effect of HOXA11-AS on the expressions of genes related to the proliferation, migration, and cell cycle. Then, VSMCs were treated with tumor necrosis factor-α (TNF-α), and the expression of HOXA11-AS was examined in VSMCs. The effect of HOXA11-AS on TNF-α-induced inflammation in VSMCs was detected as well. Finally, we analyzed the effect of HOXA11-AS on PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. RESULTS: HOXA11-AS expression was markedly increased in carotid endarterectomy specimens of symptomatic AS patients compared to that of asymptomatic AS patients. Expression levels of HOXA11-AS and pro-inflammatory genes were significantly elevated in carotid endarterectomy specimens of DM patients. Similarly, HOXA11-AS expression was also significantly increased in carotid arteries of DM mice compared with that of non-DM mice. PDGF could upregulate HOXA11-AS expression in VSMCs, which was reversed by PDGF inhibitor imatinib. HOXA11-AS knockdown could reduce the expressions of the proliferation-associated gene (PCNA) and the cycle-related genes (p21, p53), and also inhibited the proliferation and migration of VSMCs induced by PDGF. HOXA11-AS was upregulated by TNF-α. HOXA11-AS knockdown remarkably downregulated expressions of inflammation-related genes in VSMCs induced by TNF-α. In VECs, low expression of HOXA11-AS can inhibit the expression of TNF-α-induced pro-inflammatory genes and PDGF-induced vascular inflammation-related genes. Low expression of HOXA11-AS inhibited PDGF-induced activation of PI3K/AKT pathway in VSMCs and VECs. CONCLUSIONS: HOXA11-AS may participate in DAA by activating the PI3K/AKT pathway to regulate inflammation in VSMCs and VECs.

Peeking into the Black Box of Coregistration in Clinical fMRI: Which Registration Methods Are Used and How Well Do They Perform?

BACKGROUND AND PURPOSE: Interpretation of fMRI depends on accurate functional-to-structural alignment. This study explores registration methods used by FDA-approved software for clinical fMRI and aims to answer the following question: What is the degree of misalignment when registration is not performed, and how well do current registration methods perform? MATERIALS AND METHODS: This retrospective study of presurgical fMRI for brain tumors compares nonregistered images and 5 registration cost functions: Hellinger, mutual information, normalized mutual information, correlation ratio, and local Pearson correlation. To adjudicate the accuracy of coregistration, we edge-enhanced echo-planar maps and rated them for alignment with structural anatomy. Lesion-to-activation distances were measured to evaluate the effects of different cost functions. RESULTS: Transformation parameters were congruent among Hellinger, mutual information, normalized mutual information, and the correlation ratio but divergent from the local Pearson correlation. Edge-enhanced images validated the local Pearson correlation as the most accurate. Hellinger worsened misalignment in 59% of cases, primarily exaggerating the inferior translation; no cases were worsened by the local Pearson correlation. Three hundred twenty lesion-to-activation distances from 25 patients were analyzed among nonregistered images, Hellinger, and the local Pearson correlation. ANOVA analysis revealed significant differences in the coronal (P < .001) and sagittal (P = .04) planes. If registration is not performed, 8% of cases may have a >3-mm discrepancy and up to a 5.6-mm lesion-to-activation distance difference. If a poor registration method is used, 23% of cases may have a >3-mm discrepancy and up to a 6.9-mm difference. CONCLUSIONS: The local Pearson correlation is a special-purpose cost function specifically designed for T2*-T1 coregistration and should be more widely incorporated into software tools as a better method for coregistration in clinical fMRI.

Detection of a novel HLA-DRB1*12 variant, HLA-DRB1*12:68, in a Taiwanese individual.

One nucleotide substitution at residue 628 of HLA-DRB1*12:01:01:01 results in a novel allele, HLA-DRB1*12:68.

Correlation between dual-energy spectral CT imaging parameters and pathological grades of non-small cell lung cancer.

AIM: To investigate the correlation between pathological grades of non-small cell lung cancers (NSCLCs) and quantitative parameters generated in dual-energy spectral computed tomography (CT). MATERIALS AND METHODS: Fifty-three patients with NSCLCs who underwent preoperative dual-energy spectral CT imaging and surgical resection were evaluated retrospectively. These patients were divided into a low-grade group and a high-grade group based on their histopathological differentiation. In the arterial phase (AP) and venous phase (VP), iodine concentration (IC) in cancers was measured in iodine-based material decomposition images, and normalised to the IC in the aorta to calculate the normalised iodine concentration (NIC), the spectral CT curve was generated from the monochromatic images to calculate the slope of the spectral curve (λHU). Differences in quantitative parameters (NIC and λHU) were compared using the two-sample t-test. The correlations between spectral CT parameters and tumour grades were evaluated using the Spearman rank correlation analysis. Receiver operating characteristic (ROC) curves were generated to calculate their diagnostic efficacies. RESULTS: The NIC and λHU in the low-grade NSCLC group were significantly higher than those in the high-grade NSCLC group both in AP and VP (all p<0.001). There was a significant negative correlation between spectral CT parameters and pathological grades by the Spearman rank correlation (all p<0.001). ROC analysis indicated that λHU in VP provided the best diagnostic performance in distinguishing high-grade cancers from low-grade cancers (area under the ROC curve [AUC], 0.914; sensitivity, 85.7%; specificity, 84.4%). CONCLUSION: The quantitative parameters in dual-energy spectral CT imaging provide useful information to differentiate the pathological grades of NSCLCs.

A correlation study between gene polymorphism of Th cell expressed chemokine receptor CXCR3 and its ligand levels with HCV infection prognosis.

OBJECTIVE: Chemokine receptor and its ligand participate in viral immunity and HCV infection, which are important inflammatory mediators. The current study showed the different roles of Th cell secreted chemokines CXCR3, CCR5 and CCR6 in chronic liver inflammation after HCV infection. As one important chemokine receptor, the role of polypeptide property and ligand level in HCV prognosis is still unclear. This study aims to investigate gene polymorphism of chemokine genes and ligand level, and their correlation with patient liver function, to provide evidence for HCV prognosis and chronic transition mechanism. PATIENTS AND METHODS: Whole blood samples were collected. Participants were divided into chronic hepatitis, HCV cirrhosis and self-clearance groups. Chemokine level, gene polymorphism of CXCR3 gene at loci rs2280964 and liver index were measured to analyze their correlation with HCV infection or prognosis. RESULTS: Gene polymorphism of CXCR3 at loci rs22809064 is one factor-affecting prognosis of HCV patients. CG genotype at these loci is one independent risk factor affecting chronic HCV infection. IP-10, Mig and I-TAC levels were significantly elevated in chronic hepatitis group or HCV cirrhosis group (p< 0.05 compared to self-clearance group). CONCLUSIONS: Gene polymorphism at rs2280964 locus of chemokine receptor CXCR3 is one possible reason explaining differential processes of chronic transition. CXCR3 ligands IP-10, Mig and I-TAC levels were all significantly elevated in chronic hepatitis and HCV cirrhosis patients, possibly functioning as one clinical index for HCV prognosis.

Negative association between acrylamide exposure and body composition in adults: NHANES, 2003-2004.

BACKGROUND/OBJECTIVES: Acrylamide is present in mainstream cigarette smoke and in some food prepared at high temperature. Animal studies have shown that acrylamide exposure reduces body weight. Prenatal exposure to acrylamide also has been linked to reduced birth weight in human. Whether acrylamide exposure is associated with altered body compositions in adults is not clear. SUBJECTS/METHODS: We selected 3623 subjects (aged ⩾20 years) from a National Health and Nutrition Examination Survey (NHANES) in 2003-2004 to determine the relationship among hemoglobin adducts of acrylamide (HbAA), hemoglobin adducts of glycidamide (HbGA) and body composition (body measures, bioelectrical impedance analysis (BIA), dual energy x-ray absorptiometry (DXA)). Data were adjusted for potential confounding variables. RESULTS: The geometric means and 95% CI concentrations of HbAA and HbGA were 60.48 (59.32-61.65) pmol/g Hb and 55.64 (54.40-56.92) pmol/g Hb, respectively. After weighting for sampling strategy, we identified that one-unit increase in natural log-HbAA, but not HbGA, was associated with reduction in body measures (body weight, body mass index (BMI), subscapular/triceps skinfold), parameters of BIA (fat-free mass, fat mass, percent body fat, total body water) and parameters of DXA (android fat mass, android percent fat, gynoid fat/lean mass, gynoid percent mass, android to gynoid ratio). Subgroup analysis showed that these associations were more evident in subjects at younger age, male gender, whites, lower education level, active smokers and those with lower BMI. CONCLUSIONS: Higher concentrations of HbAA are associated with a decrease in body composition in the US general population. Further studies are warranted to clarify this association.

TNFα-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2+ neutrophils.

Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis factor α (TNFα)-activated MSCs significantly promoted tumor growth. However, the role of TNFα-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNFα-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNFα-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNFα-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and CXCL5) expressed by TNFα-activated MSCs efficiently recruited CXCR2+ neutrophils into tumor. These neutrophils were responsible for the pro-metastatic effect of MSCs since inhibition of this chemotaxis abolished increased neutrophil recruitment and tumor metastasis. The interaction between neutrophils and tumor cells resulted in markedly elevated metastasis-related genes by tumor cells, including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFß. Importantly, in IL8high human breast cancer samples, we also observed similar alterations of gene expression. Collectively, our findings demonstrate that TNFα-activated MSCs promote tumor metastasis via CXCR2+ neutrophil recruitment.

Tube Feeding among Elder in Long-Term Care Facilities: A Systematic Review and Meta-Analysis.

OBJECTIVE: The use of tube feeding for elderly patients with poor nutritional intake is a ubiquitous method of feeding. This systematic review and meta-analysis were carried out to compare nutritional benefits of enteral feeding versus oral feeding in long-term care facilities. SETTING: Databases including the Cochrane Library, ProQuest, PubMed, EMBASE, EBSCO, Web of Science and Google Scholar through April 2014 using keywords including enteral feeding, tube feeding or oral feeding combined with long term care facilities or nursing home. PARTICIPANTS: Eight articles, with 841 participants were included in meta-analysis and 13 articles were included in systematic review. The elderly had to live in long-term care institutions and could not be on any mechanically assisted ventilation systems or be in any type of post-operative status. MEASUREMENTS: The three investigators extracted and appraised data using the same study design, baseline characteristics, and outcomes, independently. RESULTS: Following a systematic review, 13 articles out of 8218 original research articles were selected for this analysis. Meta-analysis of tube-fed patients found lower levels of hemoglobin (Weighted Mean Difference (WMD -0.21g/dl; 95% CI -0.42 to -0.01; p=0.04) and creatinine (WMD -0.08g/dl; 95% CI -0.17 to 0.00, p=0.05). Moreover, the results showed that there were no benefits regarding body mass index (BMI), albumin, dietary intake of proteins, total calories and fat. CONCLUSIONS: The results show that tube feeding does not increase patients' nutrients absorption to improve nutritional status. Instead, these results indicate that oral feeding is better regarding some nutritional biochemical parameters.

Downregulation of CXCL12 in mesenchymal stromal cells by TGFß promotes breast cancer metastasis.

Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor ß (TGFß) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGFß. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGFß. Furthermore, silencing of CXCL12 in TGFß-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFß, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGFß regulates tumour metastasis.

Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities.

Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.

Multiple idiopathic cervical root resorption: a case report.

AIM: To report a severe and rare case of multiple idiopathic cervical root resorption (MICRR) in an adult female. SUMMARY: A healthy 27-year-old Chinese female, with no significant associated factors, presented with MICRR. Resorption progressed quickly and lesions varied in severity, involving 29 teeth and leading to the loss of 23 teeth over a period of only 3 years. The inner surface of the crown showed extensive areas with worm-eaten lacunar resorption, and the resorptive lesions had abundant lysosomes throughout their cytoplasm. Further, heavy deposits of reaction products were shown in variously sized lysosomes.

The dissemination mode of drug-resistant genes in Enterobacter cloacae.

BACKGROUND: Enterobacter cloacae (E. cloacae) infection has the highest mortality rate among Enterobacter infections. This study aimed to determine the prevalence and the transmission route of the class I integron, qnr genes, and CTX-M ESBLs genes in clinical isolates and to analyse the association between the prevalence of MDR genes and the antibiotic resistance of E. cloacae. MATERIALS AND METHODS: The antibiotic susceptibility was tested the agar dilution method. The class I integron, qnr genes, and CTX-M ESBLs genes were detected by polymerase chain reaction (PCR). The prevalence data were analysed with the Chi-square test. RESULTS: In the 100 clinical isolates, the class I integron-positive rate was 65%, with 12% on chromosome, 15% on plasmids and 38% on both. The positive rate of qnr genes was 37% with plasmid location. The positive rates for qnrA, qnrB and qnrS were 6%, 23% and 8%, respectively. The CTX-M ESBLs-positive rate was 34%. For CTX-M-1 ESBLs, 15% were on chromosome, 6% on plasmids and 4% on both; for CTX-M-9 ESBLs, 1% was on chromosome and 7% on plasmid; for CTX-M-25 ESBLs, 3% were on chromosome and 1% on plasmid. CONCLUSION: Antibiotic resistance genes may be horizontally and vertically disseminated among E. cloacae, which helps multidrug-resistant (MDR) strains of E. cloacae to be successful nosocomial agents.

Statin use reduces the risk of dementia in elderly patients: a nationwide data survey and propensity analysis.

OBJECTIVES: The objective of this study was to examine the association between the use of statins and the risk of newly diagnosed dementia in an elderly population. DESIGN, SETTING AND PARTICIPANTS: Random samples of 1,000,000 individuals covered by the National Health Insurance in Taiwan were included in the analysis. All participants were 65 years or older without dementia and either did or did not start treatment with statins from 1 August 1997 to 31 December 2010. Patients with established dementia before the start of treatment were excluded. Baseline characteristics were matched (by propensity score) in those who did and did not receive statins. RESULTS: A total of 57,669 subjects were included in the analysis with approximately 12 years of follow-up. Propensity score matching identified 2003 patients who received statins and another 2003 patients who did not with comparable baseline characteristics. Adjusted hazard ratios (HRs) for dementia were significantly inversely associated with total or daily equivalent statin dosage (total accumulated dose: HRs 0.829, 0.720 and 0.385 from T1 to T3 vs. control, P < 0.001 for trend; mean daily dose: HRs 0.667, 0.798 and 0.503 from T1 to T3 vs. control, P < 0.001). The results remained robust after propensity adjustment. CONCLUSION: Independent of traditional risk factors, there was a decrease in newly diagnosed cases of dementia in elderly patients who had received a high total or daily dose of statins. The more potent statins (e.g. atorvastatin and rosuvastatin) seemed to be particularly effective in the prevention of dementia.