TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

Enhanced recovery after surgery (ERAS) has shown effectiveness in terms of reducing the hospital stay and cost associated with open liver resection. However, the benefit of ERAS in patients undergoing laparoscopic liver resection is still unclear, and clinical studies on this topic are limited.The ERAS program for laparoscopic liver resection was used in a group of 80 patients (ERAS group). The results were compared with those in a control group of 107 patients. All patients underwent laparoscopic liver resection. The primary endpoints were the postoperative hospital stay, defined as the number of days from surgery to discharge, and the hospitalization expense. The secondary endpoints were resumption of oral intake, readmissions, and complications.The median postoperative hospital stay was 6.2 ± 2.6 days in the ERAS group, which was significantly shorter than that in the control group (9.9 ± 5.9 d; P < 0.001). The hospitalization cost was $6871 ± 2571 in the ERAS group and $7948 ± 3630 in the control group (P = 0.020). The morbidity rate was 22.5% (18 of 80 patients) in the ERAS group and 43.9% (47 of 107 patients) in the control group (P = 0.002). There were no significant differences the in rate of readmission between the 2 groups.Enhanced recovery after surgery for laparoscopic liver resection is safe and effective. Patients in the ERPS group had a shorter hospital stay, fewer complications, and lower hospital costs.

A chemical absorption-biological reduction integrated approach, which combines the advantages of both the chemical and biological technologies, is employed to achieve the removal of nitrogen monoxide (NO) from the simulated flue gas. The biological reduction of NO to nitrogen gas (N2) and regeneration of the absorbent Fe(II)EDTA (EDTA:ethylenediaminetetraacetate) take place under thermophilic conditions (50 +/- 0.5 degrees C). The performance of a laboratory-scale biofilter was investigated for treating NO(x) gas in this study. Shock loading studies were performed to ascertain the response of the biofilter to fluctuations of inlet loading rates (0.48 approximately 28.68 g NO m(-3) h(-1)). A maximum elimination capacity (18.78 g NO m(-3) h(-1)) was achieved at a loading rate of 28.68 g NO m(-3) h(-1) and maintained 5 h operation at the steady state. Additionally, the effect of certain gaseous compounds (e.g., O2 and SO2) on the NO removal was also investigated. A mathematical model was developed to describe the system performance. The model has been able to predict experimental results for different inlet NO concentrations. In summary, both theoretical prediction and experimental investigation confirm that biofilter can achieve high removal rate for NO in high inlet concentrations under both steady and transient states.

HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advancedstage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.

Biological reduction of nitric oxide (NO) from Fe(II) ethylenediaminetetraacetic acid (EDTA)-NO to dinitrogen (N(2)) is a core process for the continual nitrogen oxides (NO(x)) removal in the chemical absorption-biological reduction integrated approach. To explore the biological reduction of Fe(II)EDTA-NO, the stoichiometry and mechanism of Fe(II)EDTA-NO reduction with glucose or Fe(II)EDTA as electron donor were investigated. The experimental results indicate that the main product of complexed NO reduction is N(2), as there was no accumulation of nitrous oxide, ammonia, nitrite, or nitrate after the complete depletion of Fe(II)EDTA-NO. A transient accumulation of nitrous oxide (N(2)O) suggests reduction of complexed NO proceeds with N(2)O as an intermediate. Some quantitative data on the stoichiometry of the reaction are experimental support that reduction of complexed NO to N(2) actually works. In addition, glucose is the preferred and primary electron donor for complexed NO reduction. Fe(II)EDTA served as electron donor for the reduction of Fe(II)EDTA-NO even in the glucose excessive condition. A maximum reduction capacity as measured by NO (0.818 mM h(-1)) is obtained at 4 mM of Fe(II)EDTA-NO using 5.6 mM of glucose as primary electron donor. These findings impact on the understanding of the mechanism of bacterial anaerobic Fe(II)EDTA-NO reduction and have implication for improving treatment methods of this integrated approach.

The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β). Mechanistic dissection showed that upregulated UBQLN1 induced PGC1β degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment. Furthermore, clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival. In conclusion, we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance, which may offer new therapeutic targets and strategies for HCC patients.

LLR for large or multiple ICCs is technically safe, feasible, and oncologically effective in select patients. It provides a favorable option for patients seeking curative treatment. The minimally invasive nature will benefit these patients without compromising the oncological efficacy. Future larger-scale studies and well-designed randomized trials are warranted to evaluate this issue.

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