Phase-engineering modulation of Mn-based oxide cathode for constructing super-stable sodium storage

The Mn-based oxide cathode with enriched crystal phase structure and component diversity can provide the excellent chemistry structure for Na-ion batteries.Nevertheless,the broad application prospect is obstructed by the sluggish Na^(+)kinetics and the phase transitions upon cycling.Herein,we establish the thermodynamically stable phase diagram of various Mn-based oxide composites precisely controlled by sodium content tailoring strategy coupling with co-doping and solid-state reaction.The chemical environment of the P2/P'3 and P2/P3 biphasic composites indicate that the charge compensation mechanism stems from the cooperative contribution of anions and cations.Benefiting from the no phase transition to scavenge the structure strain,P2/P'3 electrode can deliver long cycling stability(capacity retention of 73.8%after 1000 cycles at 10 C)and outstanding rate properties(the discharge capacity of 84.08 mA h g^(-1)at 20 C)than P2/P3 electrode.Furthermore,the DFT calculation demonstrates that the introducing novel P'3 phase can significantly regulate the Na^(+)reaction dynamics and modify the local electron configuration of Mn.The effective phase engineering can provide a reference for designing other high-performance electrode materials for Na-ion batteries.

HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors

Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.

Epigenetic mechanism of Survivin dysregulation in human cancer

Survivin(coding gene BIRC5) is a dual functional protein acting as a critical inhibitor of apoptosis(IAP) and key regulator of cell cycle progression. It is usually produced in embryonic tissues during development and undetectable in most adult tissues.Overexpression of Survivin frequently occurs in various human cancers and increased Survivin correlates with poor clinic outcome, tumor recurrence, and therapeutic resistance. Because of its selective expression in tumor, but not normal tissues,Survivin has been recognized as an attractive target for cancer treatment. Although several therapeutic approaches targeting Survivin are actively under clinical trials in human cancers, to date no Survivin-targeted therapy has been approved for cancer treatment. Numerous studies have devoted to uncovering the underlying mechanism resulting in Survivin dysregulation at multiple levels, such as transcriptional and post-transcriptional regulation. The current article provides a literature review on the transcriptional and epigenetic regulation of Survivin expression in human cancers. We focus on the impact of DNA methylation and histone modifications, including specific lysine methylation, demethylation, and acetylation on the expression of Survivin.The latest development of epigenetic approaches targeting Survivin for cancer treatment are also discussed.

Understanding the biology of HER3 receptor as a therapeutic target in human cancer

HER3 belongs to the human epidermal growth factor receptor(HER) family which also includes HER1/EGFR/erb B1,HER2/erb B2,and HER4/erb B4. As a unique member of the HER family,HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases(RTKs) in cancer cells to activate oncogenic signaling,especially the PI-3 K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors.Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer:opportunities to overcome a difficult problem

Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.