Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

The Hepatorenal Toxicity and Tumor Response of Chemotherapy With or Without Aidi Injection in Advanced Lung Cancer: A Meta-Analysis of 80 Randomized Controlled Trials.

PURPOSE: Chemotherapy-induced hepatorenal toxicity often decreases tolerance for further therapies and results in poor quality of life and prognosis for patients with lung cancer. In this meta-analysis, all related studies were systematically re-evaluated to determine whether Aidi injection relieves hepatorenal toxicity and improves tumor response, and to determine its threshold and the optimal treatment regimen for obtaining the desired responses. METHODS: All studies regarding Aidi injection with chemotherapy were gathered from Chinese and English databases (from inception until January 2019). Their bias risk was evaluated and the data were synthesized using meta-analysis; the quality of evidence of all outcomes was rated by using the Grades of Recommendation Assessment, Development, and Evaluation approach. FINDINGS: Eighty randomized controlled trials containing 6279 patients were included in the study. Most of the trials showed unclear risk of bias. Aidi injection with chemotherapy increased the objective response rate (risk ratio [RR], 1.32; 95% CI, 1.25-1.40) and the disease control rate (RR, 1.15; 95% CI, 1.12-1.17) and resulted in a lower incidence of hepatotoxicity (RR, 0.61; 95% CI, 0.55-0.69) and nephrotoxicity (RR, 0.62; 95% CI, 0.53-0.72) than that of chemotherapy alone. Subgroup analyses showed that treatment with 50 mL per time, 10 to 14 days per cycle, and 2 to 3 cycles of Aidi injection with chemotherapy resulted in a low incidence of hepatorenal toxicity. All of the results were robust, and their quality was moderate. IMPLICATIONS: The moderate evidence indicates that Aidi injection with chemotherapy may improve tumor response and result in a low incidence of hepatorenal toxicity in patients with lung cancer. Aidi injection may relieve hepatorenal toxicity and exhibit an important protective effect against chemotherapy-induced hepatorenal toxicity. Based on the subgroup analysis results, Aidi injection seems to lower the threshold for chemotherapy. Treatment with 50 mL per time, 10 to 14 days per cycle, and 2 to 3 cycles may be the optimal usage for attaining a decrease in hepatorenal toxicity.

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been widely spread. We aim to investigate the clinical characteristic and allergy status of patients infected with SARS-CoV-2. METHODS: Electronic medical records including demographics, clinical manifestation, comorbidities, laboratory data, and radiological materials of 140 hospitalized COVID-19 patients, with confirmed result of SARS-CoV-2 viral infection, were extracted and analyzed. RESULTS: An approximately 1:1 ratio of male (50.7%) and female COVID-19 patients was found, with an overall median age of 57.0 years. All patients were community-acquired cases. Fever (91.7%), cough (75.0%), fatigue (75.0%), and gastrointestinal symptoms (39.6%) were the most common clinical manifestations, whereas hypertension (30.0%) and diabetes mellitus (12.1%) were the most common comorbidities. Drug hypersensitivity (11.4%) and urticaria (1.4%) were self-reported by several patients. Asthma or other allergic diseases were not reported by any of the patients. Chronic obstructive pulmonary disease (COPD, 1.4%) patients and current smokers (1.4%) were rare. Bilateral ground-glass or patchy opacity (89.6%) was the most common sign of radiological finding. Lymphopenia (75.4%) and eosinopenia (52.9%) were observed in most patients. Blood eosinophil counts correlate positively with lymphocyte counts in severe (r = .486, P < .001) and nonsevere (r = .469, P < .001) patients after hospital admission. Significantly higher levels of D-dimer, C-reactive protein, and procalcitonin were associated with severe patients compared to nonsevere patients (all P < .001). CONCLUSION: Detailed clinical investigation of 140 hospitalized COVID-19 cases suggests eosinopenia together with lymphopenia may be a potential indicator for diagnosis. Allergic diseases, asthma, and COPD are not risk factors for SARS-CoV-2 infection. Older age, high number of comorbidities, and more prominent laboratory abnormalities were associated with severe patients.

Prevalence, awareness, treatment, and control of hypertension in the non-dialysis chronic kidney disease patients.

BACKGROUND: Data on the epidemiology of hypertension in Chinese non-dialysis chronic kidney disease (CKD) patients are limited. The aim of the present study was to investigate the prevalence, awareness, treatment, and control of hypertension in the non-dialysis CKD patients through a nationwide, multicenter study in China. METHODS: The survey was performed in 61 tertiary hospitals in 31 provinces, municipalities, and autonomous regions in China (except Hong Kong, Macao, and Taiwan). Trained physicians collected demographic and clinical data and measured blood pressure (BP) using a standardized protocol. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, and/or use of antihypertensive medications. BP < 140/90 mmHg and < 130/80 mmHg were used as the 2 thresholds of hypertension control. In multivariate logistic regression with adjustment for sex and age, we analyzed the association between CKD stages and uncontrolled hypertension in non-dialysis CKD patients. RESULTS: The analysis included 8927 non-dialysis CKD patients. The prevalence, awareness, and treatment of hypertension in non-dialysis CKD patients were 67.3%, 85.8%, and 81.0%, respectively. Of hypertensive CKD patients, 33.1% and 14.1% had controlled BP to < 140/90 mmHg and < 130/80 mmHg, respectively. With successive CKD stages, the prevalence of hypertension in non-dialysis CKD patients increased, but the control of hypertension decreased (P < 0.001). When the threshold of BP < 130/80 mmHg was considered, the risk of uncontrolled hypertension in CKD 2, 3a, 3b, 4, and 5 stages increased 1.3, 1.4, 1.4, 2.5, and 4.0 times compared with CKD 1 stage, respectively (P < 0.05). Using the threshold of < 140/90 mmHg, the risk of uncontrolled hypertension increased in advanced stages (P < 0.05). CONCLUSIONS: The prevalence of hypertension Chinese non-dialysis CKD patients was high, and the hypertension control was suboptimal. With successive CKD stages, the risk of uncontrolled hypertension increased.

VIKOR method with enhanced accuracy for multiple criteria decision making in healthcare management.

Visekriterijumsko kompromisno rangiranje (VIKOR) method is one of the commonly used multi criteria decision making (MCDM) methods for improving the quality of decision making. VIKOR has an advantage in providing a ranking procedure for positive attributes and negative attributes when it is used and examined in decision support. However, we noticed that this method may failed to support an objective result in medical field because most medical data have normal reference ranges (e.g., for normally distributed data: NRR ∈ [µ ± 1.96σ], this limitation shows a negative effect on the acceptance of it as an effective decision supporting method in medical decision making. This paper proposes an improved VIKOR method with enhanced accuracy (ea-VIKOR) to make it suitable for such data in medical field by introducing a new data normalization method taking the original distance to the normal reference range (ODNRR) into account. In addition, an experimental example was presented to demonstrate efficiency and feasibility of the ea-VIKOR method, the results demonstrate the ability of ea-VIKOR to deal with moderate data and support the decision making in healthcare care management. For this reason, the ea-VIKOR should be considered for use as a decision support tool for future study.

[Mice cope with parabiosis − assessment of their physiological changes of life].

The purpose of this study was to establish a parabiotic mice model and assess the physiological changes of the mice under the parabiotic state. Thirteen pairs of isogenic partners were studied. The model was created by preparing a bridge of skin and subcutaneous tissues between the two mice starting distal of the elbow joint along the humerus along the lateral costal region until the end of the waist line. Physiological, social and affective qualities of life were studied in the mice through behavioural observations for 120 days following the parabiotic surgery. During the first 2-3 days following the operation, the animals suffered from severe pain and distress. During the following days and weeks, the physiological system began to recover and the animals displayed behavioral adaptations to the parabiotic condition. All animals survived at day 120. At three days post operation, the body weight began to decrease. Following this, the animals experienced a continual body weight recovery and reached pre-surgical measures at about 30 days post op. Forty-eight h post op., faecal corticosterone-metabolites were extremely elevated, but their levels returned to two to four times of levels in control females within 72 hours post op. The faecal corticosterone-metabolite levels decreased near to control values on day 75. Out of the 13 pairs, the blood exchange rate of three parabiotic partners was tested, with the result being normal post op. After 12 weeks, the total blood exchange between both partners needed 63 or 46 or 107 min, respectively. These results demonstrated that the animals could adapt behaviourally to the parabiotic situation. Therefore, this parabiosis mouse model may provide useful insights in many research areas, such as transplantation immunity, hematological system and metabolism, etc.

[Expression of VEGF in kidney of diabetic rats].

OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) in the kidney of diabetic rats and probe its relationship with the development of diabetic nephropathy (DN). METHODS: Diabetes mellitus was induced in SD rats by Streptozotocin. The renal tissues of rats were taken out at 2, 4, 8, 12, 16, 20 and 24 weeks after operation. The expression of VEGF was assessed by immunohistochemistry methods. VEGF mRNA in kidney was detected by RT-PCR at the same time points. The levels of VEGF mRNA and immunostaining were quantified by computer image analysis. The relationships of VEGF with the indices of renal damage, including renal/body weight, urinary protein excretion, glomerular volume and glomerular area, were analyzed. RESULTS: The expression of VEGF mRNA in diabetic kidney was significantly up-regulated after operation from 2 weeks to 24 weeks with the peak level at 20 weeks, when compared with control at the same time-points. The positive results of VEGF staining in diabetic glomeruli was increasingly observed after operation from 2 weeks to 24 weeks, with the peak at 20 weeks. The positive results of VEGF staining in diabetic tubuli was increasingly seen from 2 weeks to 24 weeks, with the peak at 8 weeks. CONCLUSION: VEGF level is increased continuously in the diabetic kidney of rat. The increased expression of VEGF is mainly located in the glomeruli at the early and middle stages, and is in the tubuli at the middle and late stages. VEGF expression in the diabetic kidney of rat is related to the development of renal changes.

[The expression and significance of the angiopoietin-1 in the kidney of diabetic rats].

OBJECTIVE: To explore the expression and significance of angiopoietin-1 (Ang-1) in the renal tissue of diabetic rats. METHODS: The SD rats were divided into the diabetic and control groups. The diabetic group was treated by streptozotocin. The expression of Ang-1 in renal tissue was detected by RT-PCR and immunohisochemistry at 2, 4, 8, 12, 16, 20 and 24 weeks. The level of Ang-1 was quantified by computer image analysis. The relationship between Ang-1 and the index of renal damage including renal/body weight, urinary protein excretion, glomerular volume, and glomerular area was analyzed. RESULTS: Ang-1 mRNA in diabetic renal tissue was significantly upregulated at 4 and 8 weeks, compared with diabetic group at other time points or control group at the same time points, and then downregulated gradually after 12 weeks. The level of Ang-1 mRNA decreased significantly as compared with control group at 24 week. Ang-1 was outstandingly expressed in glomeruli. From 4-week to 24-week, the number of Ang-1 staining in diabetic glomeruli increased significantly as compared with control group, being maximal at 4 and 8 weeks, and subsequently decreased after 12 week. Ang-1 level was correlated with renal/body weight, glomerular volume, glomerular area, and urine protein excretion, respectively. CONCLUSION: The change of Ang-1, which is early upregulation and late downregulation, exists in diabetic renal tissue. The unusual expression of Ang-1 is partly connected with the renal changes of diabetic rats.

[Expression level of cubilin in the rat model of diabetic nephropathy].

OBJECTIVE: To observe the expression level of Cubilin in the renal tubules of rats with STZ-induced diabetic nephropathy, to assess its correlation with 24 hours' albuminuria, and to investigate the mechanisms of tubular dysfunction at the early stage of diabetic nephropathy. METHODS: Diabetic nephropathy was induced in Sprague-Dalwley rats by intraperitoneal injection of STZ, while the rats of normal group were injected with normal saline. Biochemical indices of blood and urine specimens were observed in both groups at weeks 2, 4 and 6 respectively. The renal expression levels of Cubilin in the two groups were determined by immunohistochemistry and RT-PCR. RESULTS: The expression level of Cubilin in the diabetic nephropathy group was significantly decreased at week 2 after operation (P < 0.05), and it continued to decrease from week 2 to week 6. Also there was significant difference between each two time-points (P < 0.05), and the Cubilin expression level was negatively correlated with albuminuria (P < 0.01). CONCLUSION: The decreased expression level of Cubilin in early-stage diabetic nephropathy rats may partly contribute to the development of microalbuminuria. Cubilin can be regarded as one of the early markers when tubular dysfunction develops in the case of diabetic nephropathy.

[Effects of Salvia miltiorrhiza on oxidative stress and microinflammatory state in patients undergoing continuous hemodialysis].

OBJECTIVE: To investigate the effects of Salvia miltiorrhiza (SM) on oxidative stress and microinflammatory state in patients undergoing continuous hemodialysis (CHD). METHODS: Thirty-six patients who had received CHD for over half a year were assigned into the routine CHD group (18 cases) and the treated group treated with routine CHD plus SM (18 cases). Meanwhile, 18 healthy adults were taken as the normal control. Indexes related with oxidative stress [malondialdehyde (MDA), advanced oxidative protein products (AOPP) and superoxide dismutase (SOD)) and microinflammation C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were detected before and after 1, 2 and 3 months of treatment. RESULTS: The levels of AOPP, MDA, CRP, IL-6 and TNF-alpha in patients were higher and SOD was lower than those in the normal control at all the time points (P < 0.01). Compared with the baseline, the levels of AOPP and MDA in the routine CHD group significantly increased and SOD decreased after 3 months of treatment (P < 0.05), but changes of CRP, IL-6 and TNF-alpha showed no significance though there were somewhat increment (P > 0.05). The levels of AOPP and MDA were lower and SOD was higher after 1, 2 and 3 months of SM combined treatment, and CRP was lower after 3 months of treatment in the treated group than those of baselines and those at the corresponding time points in the routine CHD group (P < 0.01), but IL-6 and TNF-alpha reduced insignificantly (P > 0.05). CONCLUSION: Hemodialysis may aggravate the oxidative stress and microinflammation in patients, which could be obviously alleviated by SM.

[Effects of leukocyte depletion filter on canine kidney during cardiopulmonary bypass].

OBJECTIVE: To explore the effect of a reforming leukocyte depletion filter (LDF-1) on the functional and pathologic changes of canine kidney during cardiopulmonary bypass (CPB). METHODS: Twelve Mongolian dogs were randomly allocated into a control group (no LDF-1, n = 6) or a leukocyte-depleted filter group (LDF-1 placed in venous line, n = 6). CPB of the dogs anestheitized with sodium pentobarbitone at 25 mg/kg was set up. After 10 min of CPB, aorta was clamped and St. Thomas cardioplegic solution at 20 mg/kg was immediately injected into the root of aorta. The aortic cross-clamp was released and CPB was closed at 70 min. Dogs were observed for 2 h after weaning from CPB. LDF-1 was opened at 2 min and stoped at 7 min during initially running CPB in the LDF-1 group. Circulating leukocytes, plasma L-selectin, and plasma IL-8 were respectively counted before CPB, at 10 minutes, 40 min, and 75 min during CPB, the end of CPB, and 2 h after CPB. The urine analysis and renal pathology, which were obtained before CPB and 2 h after CPB, were observed. RESULTS: The number of leukocytes significantly decreased by 55% - 68% in the LDF-1 group compared with the baseline during CPB. The value at 10 min of CPB in the LDF-1 group was lower than that in the control group (P < 0.05). Plasma levels of L-selectin and IL-8 obviously increased in the 2 groups compared with the baseline during CPB, but both levels at 2 h after CPB in the LDF-1 group were lower than those in the control group (P <0. 05). No statistic difference was found in plasma levels of urea and creatinine, but hematuria was observed in the 2 groups at 2 hours after CPB. The pathologic changes of kidney, which was mainly renal tubule swelling accompanied partly with vacuolar degeneration, were similar under the light microscope in the 2 groups at 2 h after CPB. Obvious glomerular damage was not found. CONCLUSION: LDF-1 can effectively decrease leukocyte counts and the inflammatory reaction, but it can not bring about excellent protective effect on kidney during CPB when used alone. Attention to should be paid the renal protection in the postoperative CPB.

[The influence of leukocyte depletion filter-LD-1 on leukocytes, IL-6, MPO and the pathologic changes of myocardic tissues during cardiopulmonary bypass].

OBJECTIVE: To elucidate the influence of the leukocyte depletion filter (LD-1) on leukocytes, IL-6, myeloperoxidase enzyme (MPO) and the pathological changes of myocardic tissues during cardiopulmonary bypass(CPB). METHODS: Twelve dogs were used in this study. The LD-1, designed and made by ourselves, was fixed on the venous line in the trial group (n=6). It was used during the first 5 min after 2 min of CPB. LD-1 was not installed in the control group (n=6). Circulating leukocytes were counted before CPB, at 10 min, 40 min, 75 min during CPB, at the end of CPB, and 2 h after CPB. Plasma levels of IL-6 and MPO were also determined at the same time. The pathologic changes of left ventricular biopsies were observed before CPB, 5 min after protamine was given, and 2 h after CPB. RESULTS: The CPB 10 min WBC Count fell to 36% of that Before CPB in LD-1 group, which was lower than the WBC count in the control group synchronously (P < 0.01). But after CPB 2 h, both of them were close to the levels Before CPB in the two groups. In LD-1 group, IL-6 increased at CPB 40 min and reached to the top. But after wards it dropped continuously. The changes were of no significance in MPO and in the pathological examination of myocardic tissues (P > 0.05). CONCLUSION: The LD-1 on venous line was capable of decreasing WBC count effectively. As a result, the inflammation factors that leukocytes released were lower, so the program chain of inflammation by CPB was shorter. But LD-1 was not superior in myocardial preservation.