Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Risk factors for the recurrence of diabetic foot ulcers among diabetic patients: a meta-analysis.

This study aimed to systematically review and identify the risk factors for the recurrence of diabetic foot ulcers (DFUs) among diabetic patients. PUBMED, EMBASE, Web of Science, Cochrane Library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases were electronically searched to identify eligible studies updated to January 2019 to collect case-control studies or cohort studies on the risk factors for the recurrence of DFUs. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. A meta-analysis was performed using RevMan 5.3. Nine retrospective cohort studies were included, in which 1426 patients were enrolled, 542 in the DFU recurrence group and 884 in the non-recurrent DFU group. Risk factors for the recurrence of DFUs included male gender (odds ratio [OR] = 1.38, 95% confidence interval [CI], 1.07-1.78, P < .05), smoking (OR = 1.66, 95% CI, 1.26-2.20, P = .0004), duration of diabetes (WMD = 4.43, 95% CI, 1.96­6.90, P = .0004), duration of past DFUs (OR = 1.02, 95% CI, 1.00-1.03, P = .006), plantar ulcers (OR = 5.31, 95% CI, 4.93-5.72, P <.00001), peripheral artery disease (OR = 1.65, 95% CI, 1.20-2.28, P = .002), and diabetic peripheral neuropathy (OR = 2.15, 95% CI, 1.40-3.30, P = .0005). No significant differences were found in age, body mass index, total cholesterol, diabetic nephropathy, diabetic retinopathy, or hypertension. Health care staff should pay attention to the identified risk factors for the recurrence of DFUs. Because of the limited quality and quantity of the included studies, rigorous studies with adequate sample sizes are needed to verify the conclusion.

Effect of Orem's self-care model on discharge readiness of patients undergoing enterostomy: A randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of Orem's self-care model in preparing hospitals for the discharge of patients with colorectal cancer who undergo enterostomy. METHODS: 92 patients with enterostomy were recruited between February 2022 and February 2023 from a general tertiary hospital. The participants were assigned to either the intervention group or the control group randomly. The intervention group received Orem's self-care program and a three-month follow-up, whereas the control group received only routine care and a three-month follow-up. Discharge readiness, self-care ability, and stoma-quality-of-life data were collected at hospital discharge (T1), 30 days (T2), and 90 days (T3) after discharge. RESULTS: The intervention group had substantially higher discharge readiness (knowledge, p < 0.001; coping ability, p = 0.006; personal status, p = 0.001; expected support, p = 0.021; total score, p < 0.001), better self-care ability at T1 (self-care knowledge, p < 0.001; self-care skills, p = 0.010), better total quality of life (QoL) at T1, T2, and T3 (p < 0.001; p = 0.006; p = 0.014); better stoma management and daily routine at T1 (p = 0.004; p < 0.001); and better daily routine at T2 (p = 0.009) than the control group. CONCLUSIONS: The designed discharge readiness program based on Orem's self-care could promote effective patient discharge readiness, self-care knowledge, self-care skills, and QoL. TRIAL REGISTRATION: The trial number ChiCTR2200056302 registered on ClinicalTrials.gov.

Radiosensitivity enhancement by arsenic trioxide in conjunction with hyperthermia in the EC-1 esophageal carcinoma cell line.

OBJECTIVE: To explore the effect on radiosensitivity of arsenic trioxide (As203) in conjunction with hyperthermia on the esophageal carcinoma EC-1 cell line. METHOD: Inhibition of EC-1 cell proliferation at different concentrations of As203 was assessed using the methyl thiazolyl blue colorimetric method (MTT method), with calculation of IC50 value and choice of 20% of the IC50 as the experimental drug concentration. Blank control, As203, hyperthermia, radiotherapy group, As203 + hyperthermia, As203 + radiotherapy, hyperthermia + radiotherapy and As203 + hyperthermia + radiotherapy groups were established, and the cell survival fraction (SF) was calculated from flat panel colony forming analysis, and fitted by the 'multitarget click mathematical model'. Flow cytometry (FCM) was used to detect changes in cell apoptosis and the cell cycle. RESULTS: As203 exerted inhibitory effects on proliferation of esophageal carcinoma EC-1 cells, with an IC50 of 18.7 µmol/L. After joint therapy of As203 + hyperthermia + radiotherapy, the results of FCM showed that cells could be arrested in the G2/M phase, and as the ratio of cells in G0/G1 and S phases decreased, cell death became more pronounced. CONCLUSION: As203 and hyperthermia exert radiosensitivity effects on esophageal carcinoma EC-1 cells, with synergy in combination. Mechanistically, As203 and hyperthermia mainly influence the cell cycle distribution of EC-1 esophageal carcinoma cells, decreasing the repair of sublethal damage and inducing apoptosis, thereby enhancing the killing effects of radioactive rays.

[Flocculation of kaolin suspensions by chitosan grafted ternary polymerization flocculant].

Flocculation of kaolin suspensions using ternary polymerization flocculant (CAS) synthesized by chitosan (CTS), acrylamide and ethyl acrylate quaternary ammonium salt was investigated in lab-scale. It was found that CAS had more advantages such as higher flocculation efficiency, lesser dosage and wider pH flocculation range than CTS. CAS was insignificantly exposed to the properties of suspended particles, so preferable flocculation efficiency by it could be obtained both with distilled water and tap water kaolin suspensions. The optimal dosage for CAS was only one-tenth of that of CTS in neutral condition. Good flocculation performance was observed in the pH range of 2.0-11.0 at the dosage of 0.5 mg x L(-1) CAS, and the turbidity removal rates were about 95%. It was also shown that flocculation efficiency was very sensitive to the raw turbidity of kaolin suspensions. At less than 0.5 mg x L(-1) of CAS dose, the higher raw turbidity of the suspension contrarily yielded a lower removing rate. However, when the dosage of CAS was more than 0.5 mg x L(-1), the flocculation efficiency increased with increasing the raw turbidity of kaolin. When the dosage was more than 1.0 mg x L(-1), turbidity removal efficiencies exceeding 85% could be achieved in overall experimental turbidities from 10 to 160 NTU. iPDA-100 device was used to follow the particle aggregation process. And also zeta potential values of particles,floc sizes, shape analyses were presented. It is presumed that the flocculation induced by CAS is dominated by charge patch mechanism and bond bridging. The flocculation reactivity of kaolin suspensions exhibits a dynamic changing, which is simultaneously responsible for several kinds of driving forces.