Because of the high theoretical capacity of 1675 mAh g and high energy density of 2600 Wh kg, respectively, lithium-sulfur batteries are attracting intense interest. However, it remains an enormous challenge to realize high utilizations and loadings of sulfur in cathodes for the practical applications of Li-S batteries. Herein, we design a quasi-2D Co@N-C composite with honeycomb architecture as a multifunctional sulfur host via a simple sacrificial templates method. The cellular flake with large surface area and honeycomb architecture can encapsulate much more sulfur, leading to high sulfur content (HSC) composites, and by stacking these HSC flakes, a high sulfur loading (HSL) electrode can be realized due to their high layer bulk density. Compared to our previous work in multifunctional Co-N-C composites, the cellular Co@N-C composite displays a distinct enhancement in the sulfur content, sulfur loading, cycle stability, and rate performance. Benefiting from the cellular morphology, a composite with an HSC of 93.6 wt % and an electrode with an HSL of 7.5 mg cm can be obtained simultaneously, which exhibited excellent rate performance up to 10 C (3.6 mg cm) and great cycling stability.

Purpose: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib. Experimental Design: We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth. Results: Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH 2 -terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptorT790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S andT733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity. Conclusions: Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.

IntroductionCyclooxygenase-2 (COX-2) is believed to be an important enzyme in the carcinogenesis of hepatocellular carcinoma (HCC). However, it is still controversial whether COX-2 expression can be regarded as a prognostic factor for HCC patients. We performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of COX-2 expression in HCC.Material and methodsIdentification and review of publications assessing clinical or prognostic significance of COX-2 expression in HCC until November 1, 2014. A meta-analysis was performed to clarify the association between COX-2 expression and clinical outcomes.ResultsA total of 11 publications met the criteria and included 943 cases. Analysis of these data showed that COX-2 expression was not significantly correlated with capsular formation (OR = 0.84, 95% confidence interval (CI): 0.46–1.55, p = 0.58), tumor TNM stage (OR = 0.73, 95% CI: 0.23–2.33, p = 0.59), vascular invasion (OR = 1.04, 95% CI: 0.25–4.35, p = 0.96), tumor size (OR = 0.78, 95% CI: 0.21–2.86, p = 0.71), or tumor differentiation degree (OR = 1.08, 95% CI: 0.42–2.79, p = 0.87). However, in the identified studies, COX-2 expression was strongly associated with high alpha-fetoprotein level (OR = 1.83, 95% CI: 1.01–3.33, p = 0.05), HBsAg status (OR = 1.85, 95% CI: 1.13–3.03, p = 0.01), decreased overall survival (relative risk (RR): 1.54, 95% CI: 1.18–2.02, p = 0.001) and decreased disease-free survival (RR = 1.49, 95% CI: 1.22–1.81, p < 0.001).ConclusionsThis meta-analysis shows that COX-2 expression in HCC is associated with decreased overall and disease-free survival and thus marks a worse prognosis. Nevertheless, more large sample and well-designed studies are warranted to confirm this finding.

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