Background: HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is indicated as a tumor suppressor in some cancers, but it is highly expressed in breast cancers. Here we characterized the tumorigenic function of SH3BGRL in HER2-expressing breast cancer cells and the subsequent effect in HER2-targeted therapies. Methods: The interaction of SH3BGRL to HER2 were characterized with various truncated SH3BGRL mutants by immunoprecipitation and molecule docking simulation. The physiological roles of SH3BGRL interacting with HER2 in tumor progression and therapy implication were characterized by gain and loss of function approaches in vitro and in vivo. Immunohistochemistry was used for detections of SH3BGRL and p-HER2 (Y1196) expressions in xenografted tumors and human breast cancer tissues. Clinical relevance of SH3BGRL expression with HER2 was validated with both breast patient sample and the public data analyses. Results: Our results demonstrated that SH3BGRL directly binds with HER2 on cell membrane via its motifs α1, α2 helixes and β3 sheet, which postpones HER2 internalization upon EGF stimulation. Consequently, the association between SH3BGRL and HER2 contributed to the prolonged HER2 phosphorylation at specific tyrosine sites, especially at Y1196, and their downstream signaling activation. The relevance between SH3BGRL expression and p-HER2 (Y1196) phosphorylation was validated in both xenografted tumors and the breast cancer patient tissues. Mechanistically, SH3BGRL promoted breast tumor cell proliferation and survival, while reduced the cell sensitivity to anti-tumor drugs, especially to the HER2-targeted drugs. In contrast, Silencing SH3BGRL or inhibiting its downstream signals efficiently induced apoptosis of breast tumor cells with HER2 and SH3BGRL doubly positive expression. Database analysis also highlighted that SH3BGRL is a poor prognostic marker, especially for HER2positive breast cancers.

Background. As the most aggressive type of skin cancer, cutaneous melanoma (CM) is experiencing a rapidly rising mortality in recent years. Exploring potential prognostic biomarkers or mechanisms of disease progression therefore has a great significance for CM. The purpose of this study was to identify genetic markers and prognostic performance of N6-methyladenosine (m6A) regulators in CM. Method. Gene expression profiles, copy number variation (CNV), and single nucleotide polymorphism (SNP) data of patients were obtained from The Cancer Genome Atlas (TCGA) database. Results. Genomic variation and association analysis of gene expressions revealed a high degree of genomic variation in the presence of m6A-regulated genes. m6A patients with high-frequency genomic variants in the regulatory gene tended to develop a worse prognosis ( p < 0.01 ). Unsupervised cluster analysis of the expression profiles of m6A-regulated genes identified three clinically distinct molecular subtypes, including degradation-enhanced subgroup and immune-enhanced subgroup, with significant prognostic differences ( p = 0.046 ). A novel prognostic signature, which was established according to m6A-related characteristic genes identified through genome-wide expression spectrum, could effectively identify samples with poor prognosis and enhanced immune infiltration, and the effectiveness was also verified in the dataset of the chip. Conclusion. We identified genetic changes in the m6A regulatory gene in CM and related survival outcomes. The findings of this study provide new insights into the epigenetic understanding of m6A in CM.

The pathogenesis of Alzheimer’s disease (AD) is complex as various mechanisms interact with each other and, therefore, intervention from a single target is often ineffective. Many studies have shown that herbal medicines, such as curcumin, fisetin, icariin, and ginsenosides, have significant intervention effects on AD with different treatment mechanisms. Therefore, we have designed this study to know whether the combination of these herbal medicines can have an intervention effect on AD through multiple targets. Amyloid precursor protein/presenilin 1(APP/PS1) double transgenic AD mice were used to study the protective effects of a combination of curcumin, piperine, icariin, and ginsenosides, as well as a combination of fisetin, piperine, icariin, and ginsenosides, which were separately mixed into the feed. These herbal medicinal compounds (HMCs) lowered the serum lipid levels, reduced the Aβ oligomers, decreased the pS404-tau protein, as well as neurofibrillary tangles, and restored the reduction of synaptic protein levels and neuronal death of AD mice without causing toxicity to liver and kidneys. In this study, we found that HMCs have significant intervention against AD through multiple targets, providing a novel therapeutic idea for the prevention of AD.

BACKGROUND Infantile hemangiomas (IHs) are the most common childhood benign tumors, showing distinctive progression characteristics and outcomes. Due to the high demand for aesthetics among parents of IH babies, early intervention is critical in some cases. β-Adrenergic blockers and corticosteroids are first-line medications for IHs, while itraconazole, an antifungal medicine, has shown positive results in recent years. CASE SUMMARY In the present study, itraconazole was applied to treat two IH cases. The therapeutic course lasted 80-90 d, during which the visible lesion faded by more than 90%. Moreover, no obvious side effects were reported, and the compliance of the baby and parents was desirable. CONCLUSION Although these outcomes further support itraconazole as an effective therapeutic choice for IHs, large-scale clinical and basic studies are still warranted to improve further treatment.

No abstract