Promising dawn in tumor microenvironment therapy: engineering oral bacteria.

Despite decades of research, cancer continues to be a major global health concern. The human mouth appears to be a multiplicity of local environments communicating with other organs and causing diseases via microbes. Nowadays, the role of oral microbes in the development and progression of cancer has received increasing scrutiny. At the same time, bioengineering technology and nanotechnology is growing rapidly, in which the physiological activities of natural bacteria are modified to improve the therapeutic efficiency of cancers. These engineered bacteria were transformed to achieve directed genetic reprogramming, selective functional reorganization and precise control. In contrast to endotoxins produced by typical genetically modified bacteria, oral flora exhibits favorable biosafety characteristics. To outline the current cognitions upon oral microbes, engineered microbes and human cancers, related literatures were searched and reviewed based on the PubMed database. We focused on a number of oral microbes and related mechanisms associated with the tumor microenvironment, which involve in cancer occurrence and development. Whether engineering oral bacteria can be a possible application of cancer therapy is worth consideration. A deeper understanding of the relationship between engineered oral bacteria and cancer therapy may enhance our knowledge of tumor pathogenesis thus providing new insights and strategies for cancer prevention and treatment.

Acute kidney injury in hospitalized adults with chronic kidney disease: comparing cROCK, KDIGO, and combined criteria.

BACKGROUND: Acute-on-chronic kidney disease (ACKD) increases the risk of progression of chronic kidney disease (CKD). This study aimed to evaluate the ability of a novel criteria of reference change value of the serum creatinine optimized criteria for acute kidney injury in CKD (cROCK) to detect ACKD patients. METHODS: This was a retrospective observational study with a 3-year follow-up. All included patients with CKD stage 3 were evaluated using cROCK, Kidney Disease Improving Global Outcomes (KDIGO), and their combined criteria. The renal composite endpoints, major adverse cardiovascular events (MACEs), and all-cause mortality were recorded as clinical outcomes. RESULTS: A total of 812 patients was enrolled. The cROCK criteria detected more ACKD events than did the KDIGO (68.0% vs. 59.5%, p < 0.001). Compared to KDIGO (-) & cROCK (-) group, ACKD patients diagnosed by cROCK had significantly higher hazard ratio [HR] for renal composite endpoints (HR, 3.591; p < 0.001), MACEs (HR, 1.748; p < 0.001), and all-cause mortality (HR, 2.985; p < 0.001). The patients in KDIGO (+) & cROCK (+) group had the lowest survival probability when considering renal composite endpoints, MACEs, and all-cause mortality (all p < 0.001). Furthermore, cROCK resulted in the largest area under the receiver operating characteristic curve (AUC) for predicting renal composite endpoints, and the combined criteria led to the largest AUC for predicting MACEs and allcause mortality. CONCLUSION: Compared to the KDIGO, the cROCK detected more ACKD events. Combining both cROCK and KDIGO criteria might improve the predictive ability for long-term outcomes in ACKD patients.

The indicative role of inflammatory index in the progression of periodontal attachment loss.

OBJECTIVE: To explore the forewarning immunological indicators during periodontal attachment loss progression in American adults. METHODS: A total of 5744 participants with periodontal attachment loss were enrolled from the National Health and Nutrition Examination Surveys (NHANES) 2009-2014. In which, dependent variable was the counts of teeth with severe attachment loss (depth of periodontal probing was above 5 mm). Independent variables were circulatory immunological indexes, including counts of white blood cells (WBC), Lymphocytes, Monocytes, Neutrophils, Eosinophils, and Basophils. The association among variables was examined using multivariable linear regression models, fitting with smoothing curves, and generalizing additive models. RESULTS: Based on the indicators of 5744 subjects, we found that severe attachment loss tended to occur in the elderly or males and was accompanied by higher WBC, Monocytes, and Neutrophils, as well as lower poverty-income ratio and educational qualification. WBC (above the inflection point: 6200 cells/µL) and Neutrophils (above the inflection point: 3300 cells/µL) counts were positively associated with attachment loss progression in each multivariable linear regression model. On subgroup analyses, stratified by sex and race, the positive correlation of WBC or Neutrophils with severe attachment loss was stable in both men and women, as well as in all races except blacks (WBC ß = - 0.0576, 95% CI - 0.1945 to 0.0793, Neutrophils ß = - 0.0527, 95% CI - 0.2285 to 0.1231). CONCLUSION: Increasing WBC (above 6200 cells/µL) and Neutrophils (above 3300 cells/µL) counts were risk indicators of severe periodontal attachment loss among all races, except in blacks.

Degradation of Ubiquitin-Editing Enzyme A20 following Autophagy Activation Promotes RNF168 Nuclear Translocation and NF-κB Activation in Lupus Nephritis.

The correlation between ubiquitin-editing enzyme A20 and E3 ubiquitin ligase ring finger protein (RNF) 168 has been reported to be critical for repair of DNA damage. This study aimed to evaluate the potential role of this regulatory interaction in the pathogenesis of lupus nephritis (LN). The expression of RNF168 and A20 was measured in the podocytes derived from MRL/lpr murine lupus as well as patients with LN. Cell-based studies using renal podocytes bearing silenced RNF168, over-expressed A20, autophagy-related gene (Atg) 5 (a ubiquitin-like modifier), or silenced Atg5 were used to assess the effect of RNF168, A20, and Atg5 on DNA damage repair and nuclear factor kappa-B (NF-κB) activation in LN. It was found that podocyte autophagy was over-activated in LN and the abnormal podocyte autophagy led to down-regulation of A20, up-regulation of RNF168, and activation of the NF-κB. RNF168 silencing or A20 restoration inhibited activation of NF-κB pathway and promoted repair of DNA damage, where the level of autophagy was not changed. Activated A20 in podocytes weakened the promoting action of cell autophagy on RNF168. The current results suggest that RNF168 dysfunction may be involved in the pathogenesis of LN via down-regulation of A20 expression. Autophagy and RNF168 may be therapeutic targets for the prevention and treatment of LN.

Effect of different hemodialysis modalities on hepcidin clearance in patients undergoing maintenance hemodialysis.

INTRODUCTION: Hepcidin is a master regulator of iron utilization and takes part in the pathophysiology of anemia in maintenance hemodialysis (MHD) patients. Hepcidin is a moderate-molecular-weight substance and partially binds to plasma proteins in the circulation, which theoretically might be removed efficiently by hemoperfusion (HP). This study aimed to compare the effect of different dialysis modalities on hepcidin removal and discuss its effect on the iron and anemia status in MHD patients. MATERIALS AND METHODS: In a longitudinal interventional study of 26 stable MHD patients, the serum hepcidin, ß2-microglobulin (ß2-MG), and intact parathyroid hormone (iPTH) were measured before and after one treatment session of hemodialysis (HD), hemodiafiltration (HDF), HD + HP, and HDF + HP, separately. One-way analysis of variance (ANOVA) was used to identify the effect of dialysis modalities on the intra-dialysis clearance ratios. RESULTS: The combined dialysis modalities (HD + HP and HDF + HP) achieved greater clearance ratios of serum hepcidin than HD and HDF alone, HD + HP vs. HD (16 ± 15% vs. 4 ± 13%, p < 0.001), HDF + HP vs. HDF (18 ± 5% vs. 10 ± 13%, p = 0.0036). Similarly, the combined dialysis modalities also performed better than HD and HDF alone in removing ß2-MG. There was no significant difference in iPTH clearance among these four modalities, except that HDF + HP achieved a greater clearance ratio than HD. Furthermore, the anemia was improved after the 6-month treatment with regular HD/HDF plus HP, which was indicated by increasing hemoglobin (p = 0.0004) and reduction of erythropoiesis-stimulating agents (ESAs) resistance index (ERI) (p = 0.0431). CONCLUSIONS: Our findings suggest that the combined dialysis modalities of HD/HDF plus HP could achieve better clearance ratios of hepcidin than HD/HDF alone, thereby, might improve iron utilization, and benefit anemia management in MHD patients. Further studies with larger sample-size patients and longer follow-up duration are still needed.

Prediction models for risk of diabetic kidney disease in Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Diabetic kidney disease (DKD) is a common and serious complication in patients with diabetic mellitus (DM), the risk of cardiovascular events and all-cause mortality also increases in DKD patients. This study aimed to detect the influencing factors of DKD in type 2 DM (T2DM) patients, and construct DKD prediction models and nomogram for clinical decision-making. METHODS: A total of 14,628 patients with T2DM were included. These patients were divided into pre-DKD and non-DKD groups, depending on the occurrence of DKD during a 3-year follow-up from first clinic attendance. The influencing indicators of DKD were analyzed, the prediction models were established by multivariable logistic regression, and a nomogram was drawn for DKD risk assessment. RESULTS: Two prediction models for DKD were built by multivariate logistic regression analysis. Model 1 was created based on 17 variables using the forward selection method, Model 2 was established by 19 variables using the backward elimination method. The Somers' D values of both models were 0.789. Four independent predictors were selected to build the nomogram, including age, UACR, eGFR, and neutrophil percentages. The C-index of the nomogram reached 0.864, suggesting a good predictive accuracy for DKD development. CONCLUSIONS: Our prediction models had strong predictive powers, and our nomogram provided visual aids to DKD risk calculation, which was simple and fast. These algorithms can provide early DKD risk prediction, which might help to improve the medical care for early detection and intervention in T2DM patients, and then consequently improve the prognosis of DM patients.

Serum Hepcidin-25 and All-Cause Mortality in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND: Hepcidin plays an important role in iron homeostasis, inhibits intestinal iron absorption and iron release from hepatocytes and macrophages, while its clinical utility remained unclear. This study aimed to investigate the associations between hepcidin-25 and mortality in MHD patients. METHODS: This was a prospective observational cohort of 161 MHD patients, with 2-year follow-up. We investigated the relationships between the variables in our dataset, including serum hepcidin-25, demographic characteristics as well as other clinical parameters. RESULTS: The median value of baseline serum hepcidin-25 was 31.0 (12.1, 57.3) ng/mL; therefore, the patients were stratified into two groups (low-level hepcidin-25 group, and high-level hepcidin-25 group). The serum iron, serum ferritin, transferrin saturation (TSAT), and hsCRP were higher, pre-dialysis creatinine and albumin were lower, and the scores of health-related qualities of life were worse in the high-level hepcidin-25 group than in the low-level hepcidin-25 group. Maximal information-based nonparametric exploration analysis suggested that serum hepcidin-25 was associated with ferritin, TSAT, and all-cause mortality. The patients with hepcidin-25<31 ng/mL had better survival outcomes than those with hepcidin-25≥31 ng/mL during the 24-month follow-up (Log rank test, P = 0.0017). For per 10ng/mL increase of serum hepcidin-25, the hazard ratio (HR) for all-cause mortality was 1.225 (95% confidence interval [CI]1.085-1.382, P<0.001), which remained significant after multivariate adjustments. CONCLUSION: Serum hepcidin-25 was associated with ferritin and TSAT, and could be an independent predictor for all-cause mortality in MHD patients. Further research with larger sample size and longer-term follow-up is still needed.

Comparison of bias and accuracy using cystatin C and creatinine in CKD-EPI equations for GFR estimation.

BACKGROUND: The directly measured glomerular filtrate rate (mGFR) is the gold standard for kidney function, but it is invasive and costly. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been widely used to estimate GFR, however, the comparative accuracy of estimated GFR (eGFR) using creatinine and cystatin C in CKD-EPI equations remains unclear. We performed this meta-analysis to assess the bias and accuracy of eGFR using equations of CKD-EPIcrea, CKD-EPIcys, and CKD-EPIcrea/cys in adult populations relevant to primary health care. METHODS: Pubmed, Web of Science, EMBASE, and the Cochrane Library were searched from inception until December 2019 for related studies. RESULTS: A total of 35 studies with 23,667 participants, which reported the data on the bias, and/or P30, and/or R were included. The difference in the bias of eGFR using CKD-EPIcys was 4.84 mL/min/1.73 m2 (95% CI, 1.88~7.80) lower than using CKD-EPIcrea, and 1.50 mL/min/1.73 m2 (95% CI, 0.05~2.95) lower than using CKD-EPIcrea/cys. These gaps increased in subgroups of low mGFR (<60 mL/min/1.73 m2). CKD-EPIcrea/cys eGFR achieved the highest accuracy, 7.50% higher than CKD-EPIcrea (95% CI, 4.81~10.18), and 3.21% higher than CKD-EPIcys (95% CI, -0.43~6.85); and the best correlation with mGFR, with Fisher's z transformed R of 1.20 (95% CI, 0.89-1.50). CONCLUSIONS: CKD-EPIcrea/cys and CKD-EPIcys gave less bias and more accurate estimates of mGFR than CKD-EPIcrea. More variables and coefficients could be added in CKD-EPI equations to achieve less bias and more accuracy in future research.