Assessment of toxic mechanisms and mode of action to three different levels of species for 14 antibiotics based on interspecies correlation, excess toxicity, and QSAR.

Antibiotics have received much attention owing to their ecotoxicity toward nontarget aquatic creatures. However, the mode of action (MOA) of toxicity against nontarget organisms is unclear in some aquatic organisms. In this study, the comparison of toxicities through interspecies correlations, excess toxicity calculated from toxicity ratio, and quantitative structure-activity relationship (QSAR) was carried out to investigate the MOAs for 14 antibiotics among Daphnia magna, Vibrio fischeri, and Pseudokirchneriella subcapitata. The results showed that interspecies toxicity correlations were very poor between any two of the three species for the 14 antibiotics. The toxicity ratio revealed that most antibiotics exhibited excess toxicity to algae and Daphnia magna but not to V. fischeri, demonstrating that some antibiotics share the same MOA, but some antibiotics share different MOAs among the three different levels of species. P. subcapitata was the most sensitive species, and V. fischeri was the least sensitive species. This is because of the differences in the biouptake and interactions of antibiotics with the target receptors between the three different trophic levels of the species. Molecular docking simulations suggested that the toxicity of antibiotics depends highly on their interactions with target receptors through hydrogen bonds, electrostatic or polar interactions, π bond interactions, and van der Waals forces. QSAR models demonstrated that hydrogen bonding and electrophilicity/nucleophilicity play key roles in the interaction of antibiotics with different receptors in the three species. The toxic mechanisms of antibiotics are attributed to the interactions between electrophilic antibiotics and biological nucleophiles, and hydrogen-bond interactions. These results are valuable for understanding the toxic mechanisms and MOA of the three different levels of species.

Effects of Education and Income on Incident Type 2 Diabetes and Cardiovascular Diseases: a Dutch Prospective Study.

BACKGROUND: Education and income, as two primary socioeconomic indicators, are often used interchangeably in health research. However, there is a lack of clear distinction between these two indicators concerning their associations with health. OBJECTIVE: This study aimed to investigate the separate and combined effects of education and income in relation to incident type 2 diabetes and cardiovascular diseases in the general population. DESIGN AND PARTICIPANTS: Participants aged between 30 and 65 years from the prospective Dutch Lifelines cohort study were included. Two sub-cohorts were subsequently created, including 83,759 and 91,083 participants for a type 2 diabetes cohort and a cardiovascular diseases cohort, respectively. MAIN MEASURES: Education and income level were assessed by self-report questionnaires. The outcomes were incident type 2 diabetes and cardiovascular diseases (defined as the earliest non-fatal cardiovascular event). KEY RESULTS: A total of 1228 new cases of type 2 diabetes (incidence 1.5%) and 3286 (incidence 3.6%) new cases of cardiovascular diseases were identified, after a median follow-up of 43 and 44 months, respectively. Low education and low income (<1000 euro/month) were both positively associated with a higher risk of incident type 2 diabetes (OR 1.24 [95%CI 1.04-1.48] and OR 1.71 [95%CI 1.30-2.26], respectively); and with a higher risk of incident cardiovascular diseases (OR 1.15 [95%CI 1.04-1.28] and OR 1.24 [95%CI 1.02-1.52], respectively); independent of age, sex, lifestyle factors, BMI, clinical biomarkers, comorbid conditions at baseline, and each other. Results from the combined associations of education and income showed that within each education group, a higher income was associated with better health; and similarly, a higher education was associated with better health within each income group, except for the low-income group. CONCLUSIONS: Education and income were both independently associated with incident type 2 diabetes and cardiovascular diseases. The combined associations of these two socioeconomic indicators revealed that within each education or income level, substantial health disparities existed across strata of the other socioeconomic indicator. Education and income are two equally important socioeconomic indicators in health, and should be considered simultaneously in health research and policymaking.

A phase III, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer.

BACKGROUND: ASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor. PATIENTS AND METHODS: This global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile. RESULTS: Patients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6-11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8-NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4-39.0) versus 47.9% (95% CI 41.7-54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib. CONCLUSIONS: First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib. CLINICALTRIAL.GOV NUMBER: NCT02588261.

Inhibition of Polo-Like Kinase 1 by BI2536 Reverses the Multidrug Resistance of Human Hepatoma Cells In Vitro and In Vivo.

BACKGROUND: Multi Drug Resistance (MDR) is the phenomenon that cancers develop resistance to majority of chemotherapy drugs and is a serious obstacle to the treatment for Hepatocellular Carcinoma (HCC). Polo-Like Kinase 1 (PLK1) is a serine/threonine kinase associated with tumor growth and clinical prognosis in HCC and BI2536 is its potent inhibitor with IC50 of 0.83nM. AIMS: To test whether the down-regulation of PLK1 by its inhibitor BI2536 would have beneficial effects on the reversal of MDR in HCC cells. METHODS: The CCK-8 assay was used to determine the viability of HepG2/ADM and SMMC7721/ADM cells and their parental cells treated with BI2536. Then animal model studies were performed. Cell invasion assay and wound healing assay were used to determine the invasion ability and motility. Flow cytometric was used to test the apoptosis induced by BI2536. Western blot and quantitative real-time PCR were performed to test the change of expression of MDR and apoptosis-related gene. RESULTS: BI2536 down-regulated the expression of PLK1 protein and mRNA specifically. BI2536 can significantly reduce IC50 for ADM and other drugs in ADM-resistant HCC cells. Meanwhile, it inhibited cell viability, proliferation, and invasion, and induced cell cycle arrest and apoptosis in HCC cells with MDR. CONCLUSION: Our results suggest that PLK1 inhibitor BI2536 can re-sensitize HCC cancer cell with MDR through induction of apoptosis. Thus, PLK1 inhibitor BI2536 may act as an effective chemotherapeutic drug in the clinical treatment of HCC patients with MDR.

SENSITIVITY OF FOUR SIMPLE METHODS TO SCREEN CHINESE PATIENTS FOR DIABETIC PERIPHERAL NEUROPATHY.

CONTEXT: Diabetic peripheral neuropathy (DPN) is a common complication associated with long-term type 2 diabetes mellitus, although early diagnosis can improve prognosis. OBJECTIVE: Our objective was to develop a simple protocol for early diagnosis of DPN in Chinese type 2 diabetic patients. SUBJECTS AND METHODS: A total of 209 type 2 diabetic patients were included; these patients were categorized as symptomatic and asymptomatic group based on their symptoms. Clinical data of these patients were recorded and they were screened for DPN by vibration perception threshold test (VPT), 10-G nylon monofilament test, temperature identification, and the tendon reflex test. RESULTS: The total combined rate of patients who were tested positive for DPN with all four screening methods was 68.7%. Patients tested positive for DPN were significantly older and had a longer disease duration than those who were tested negative (p<0.01); however, glycated hemoglobin levels, presence of hypertension, and gender did not differ significantly between them (p>0.05). Among screening methods, the highest positive rate observed among patients screened with the VPT test was 63.64% as compared to other tests. The total positive rate for temperature discrimination, 10-G monofilament and tendon reflex test were 26.79%, 11.96 % and 17.22 % respectively. In asymptomatic group VPT showed the highest positive rate for DPN (48.41%). CONCLUSIONS: The combination of four simple methods can improve the detection rate of DPN and identify subclinical cases. Abnormal vibration perception was the most common feature of DPN and it was associated with both disease duration and the age of the patient.

Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma.

PURPOSE: We conducted a Phase II clinical trial with randomized patients to determine whether autologous formalin-fixed tumor vaccine (AFTV) protects against postsurgical recurrence of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Forty-one patients with HCC who had undergone curative resection were randomly allocated to the vaccine treatment (n = 19) or no adjuvant control group (n = 22). Three intradermal vaccinations were administered at 2-week intervals beginning 4-6 weeks after hepatic resection. A delayed-type hypersensitivity test was performed before and after vaccination. Primary and secondary end points are recurrence-free survival and overall survival, respectively. Observation continued until the majority of surviving patients had lived >12 months after the curative resection. RESULTS: In a median follow-up of 15 months, the risk of recurrence in vaccinated patients was reduced by 81% (95% confidence interval, 33-95%; P = 0.003). Vaccination significantly prolonged the time to first recurrence (P = 0.003) and improved recurrence-free survival (P = 0.003) and overall survival rates (P = 0.01). AFTV played a significant role in preventing recurrence in patients with small tumors. Adverse effects were limited to grade 1 or 2 skin toxicities such as erythema, dry desquamation, and pruritus. CONCLUSIONS: AFTV therapy is a safe, feasible, and effective treatment for preventing postoperational recurrence of HCC. Patients with low tumor burdens benefit from the treatment. This treatment should be advanced to a large-scale randomized trial.