Analysis of Salt Stress on Soil Microbial Community Composition and Its Correlation with Active Components in the Rhizosphere of Acanthopanax senticosus.

Salt stress can adversely affect plant seed germination, growth and development, and eventually lead to slow growth and even death of plants. The purpose of this study was to investigate the effects of different concentrations of NaCl and Na2SO4 stress on the physicochemical properties, enzyme activities, rhizosphere microbial community and seven active components (L-phenylalanine, Protocatechuic acid, Eleutheroside B, Chlorogenic acid, Caffeic acid, Eleutheroside E, Isofraxidin) of Acanthopanax senticosus rhizosphere soil. Statistical analysis was used to explore the correlation between the rhizosphere ecological factors of Acanthopanax senticosus and its active components. Compared with Acanthopanax senticosus under NaCl stress, Na2SO4 generally had a greater effect on Acanthopanax senticosus, which reduced the richness of fungi in rhizosphere soil and adversely affected the content of multiple active components. Pearson analysis showed that pH, organic matter, ammonium nitrogen, available phosphorus, available potassium, catalase and urease were significantly correlated with active components such as Caffeic acid and Isofraxidin. There were 11 known bacterial genera, 12 unknown bacterial genera, 9 known fungal genera and 1 unknown fungal genus significantly associated with the active ingredient. Salt stress had great changes in the physicochemical properties, enzyme activities and microorganisms of the rhizosphere soil of Acanthopanax senticosus. In conclusion, different types and concentrations of salts had different effects on Acanthopanax senticosus, and the active components of Acanthopanax senticosus were regulated by rhizosphere soil ecological factors.

Recognition of the organ-specific mutations in metastatic breast cancer by circulating tumor cells isolated in vivo.

The failure to treat and control the growth of metastases is the main cause of death in breast cancer (BC) patients. Compared to the traditional method of analyzing circulating tumor DNA (ctDNA), capturing intact circulating tumor cells (CTCs) allows us to more accurately characterize mutations and identify suitable targeted therapies. We used CellCollector to collect peripheral CTCs. Thirty metastatic breast cancer (MBC) patients were enrolled, and 17 were analyzed with next-generation sequencing (NGS) methods. Clinical characteristics were analyzed along with the CTCs enumeration and detection rates. Whole-genome amplification (WGA) was used to amplify the CTC genomic DNA of 127 genes. Patients younger than 45 years old, with brain metastasis, with three or more metastatic sites, or with HER2-positive had the highest number of CTCs collected. The CTCs detection rate was also correlated to the number of metastasis sites. Different metastasis sites such as the brain, viscus, bone, and soft tissue contained specific high-frequency gene mutations. AKT3, MYC, and NT5C2 mutations were only found in brain metastases. APC, BCL2L11, ESRP1, FLT3 mutations were only in the visceral metastases. KEAP1, KIT, MET were the specific mutation genes in patients with bone and soft tissue metastases. These findings provide evidence that we can detect gene mutation information for obtaining the biological characteristics by CTCs using CellCollector. Different metastasis sites contain specific high-frequency mutation genes, which provide guidance to the accurate gene therapy.

Clinic-Pathological Features of Breast Ductal Carcinoma in Situ with Micro-Invasion.

Background: To investigate the differences of clinic-pathological features among ductal carcinoma in situ (DCIS), ductal carcinoma in situ with micro-invasion (DCIS-MI) and early invasive carcinoma (IDC) in stage T1.Methods: From January 2014 to December 2018, 308 cases DCIS, DCIS-MI 92 cases and 111 cases of T1a, 343 cases of T1b, and 1032 cases of T1c were investigated in a retrospective analysis. The population and clinic-pathological characteristics including age, menstrual status, surgical mode, lymph node status and molecular markers were compared in each group. Survival rate of all patients were followed-up for 5 years.Results: Compared with DCIS-MI group, the higher breast-conserving rate and lower lymph node metastasis rate in the DCIS group were shown in the DCIS-MI group (p < .05). There were no significant differences in tumor diameter, number of tumors, ER, PR, HER2 and Ki67 expression, molecular typing, (p > .05). The expression of Ki67 in T1a, T1b and T1c groups increased gradually with elevated grades (p < .05). The proportion of HER2-positive patients in DCIS-MI group was significantly higher than that in T1a-b-c (p < .05). There were no significant differences in DFS and OS between the 3 groups (p > .05).Conclusions: The clinic-pathological features of DCIS-MI are similar to those of DCIS and T1a, but significantly different from T1c.

The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8.

Tamoxifen, an important endocrine therapeutic agent, is widely used for the treatment of estrogen receptor positive (ER+) breast cancer. However, de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments. In this study, we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance. HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells. Moreover, high expression of HSPB8 associates with poor prognosis in ER+ breast cancer patients but not in patients without classification. Stimulating ER signaling by heterogeneous expression of ERa or 17ß-estradiol promotes HSPB8 expression and reduces the cell population in G1 phase. In contrast, blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8. In addition, knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G1 phase. AZD8055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells, which was associated with down-regulation of HSPB8. We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER+ breast cancer cells. Thus, AZD8055 was able to overcome tamoxifen resistance in breast cancer cells, and the expression of HSPB8 may predict the efficacy of AZD8055 in ER+ breast cancer. This hypothesis deserves further investigation.

HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer.

mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3-kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS-1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down-regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up-regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA-MB-468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer.

Engineering the protein corona: Strategies, effects, and future directions in nanoparticle therapeutics.

Nanoparticles (NPs) serve as versatile delivery systems for anticancer, antibacterial, and antioxidant agents. The manipulation of protein-NP interactions within biological systems is crucial to the application of NPs in drug delivery and cancer nanotherapeutics. The protein corona (PC) that forms on the surface of NPs is the interface between biomacromolecules and NPs and significantly influences their pharmacokinetics and pharmacodynamics. Upon encountering proteins, NPs undergo surface alterations that facilitate their clearance from circulation by the mononuclear phagocytic system (MPS). PC behavior depends largely on the biological microenvironment and the physicochemical properties of the NPs. This review describes various strategies employed to engineer PC compositions on NP surfaces. The effects of NP characteristics such as size, shape, surface modification and protein precoating on PC performance were explored. In addition, this study addresses these challenges and guides the future directions of this evolving field.

HER-2 ultra-low breast cancer: exploring the clinicopathological features and prognosis in a retrospective study.

Objective: To explore the clinicopathological features of patients with ultra-low expression of human epidermal growth factor 2 (HER-2) in breast cancer and its impact on prognosis. Methods: Data from 1024 patients with primary breast cancer having HER-2 ultra-low expression from January 01, 2018, to December 31, 2018, were collected and analyzed retrospectively. The clinicopathological features and prognosis were compared using a chi-squared test or Fisher exact probability method. COX regression analysis and log-rank test were used to explore the factors related to the postoperative 5-year survival rate. All analytical data were defined as statistically significant (P < 0.05). Results: Overall survival (OS) was higher in the HER-2 ultra-low group compared to the low expression group (P = 0.022). The tumor diameter, lymph node metastasis (LNM), and Ki67 expression were factors affecting DFS in the HER-2 ultra-low expression group (P < 0.05). The tumor diameter and LNM were risk factors affecting the OS (P < 0.05) in the HER-2 ultra-low expression group. LNM and Ki67 expression were risk factors affecting DFS (P < 0.05) in the HER-2 low expression group. LNM was considered an independent risk factor affecting OS (P < 0.05). Conclusion: Breast cancer with HER-2 ultra-low expression has differences in the clinicopathological features. Breast cancer with HER-2 low expression is more aggressive and has a worse prognosis. This study provides a reference to consider in the treatment of HER-2-low and -ultra-low expression breast cancer.

KIF20A is a Prognostic Marker for Female Patients with Estrogen Receptor-Positive Breast Cancer and Receiving Tamoxifen as Adjuvant Endocrine Therapy.

Purpose: Our aim was to verify whether KIF20A has the potential to serve as a prognostic marker for female patients with estrogen receptor (ER)-positive breast cancer (BC) and treated with tamoxifen (TAM). Patients and Methods: Online tools were used to investigate the potential correlation between KIF20A gene expression and survival of patients with ER-positive BC and TAM treatment. Furthermore, immunohistochemistry (IHC) was conducted to assess the expression levels of KIF20A in patients included from our center. The prognostic value of KIF20A for disease-free survival (DFS) and overall survival (OS) was further evaluated using Cox regression analysis. Results: According to the results obtained from online tools, it was found that patients with low KIF20A expression exhibited significantly better survival outcomes in terms of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and OS compared to those with high KIF20A expression (P < 0.001, P < 0.001, and P = 0.008, respectively). Additionally, significantly lower gene expression of KIF20A was found in patients who responded to TAM than in those who did not respond to TAM (P < 0.001). We further included 203 patients with adjuvant TAM therapy, and IHC for KIF20A was performed on sections from paraffin-embedded blocks. Patients with low KIF20A expression had significantly better DFS and OS (P = 0.001 and 0.002, respectively, log rank test), and the expression of KIF20A was identified as an independent factor for predicting both DFS and OS (P = 0.001 and 0.008, respectively). Conclusion: KIF20A expression is an independent prognostic factor for survival in patients with ER-positive BC who received adjuvant TAM therapy. In clinical practice, IHC evaluation of KIF20A expression in surgical samples before administering tamoxifen may assist in predicting the treatment outcomes of these patients.

CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer.

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors.

Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

PSME2 identifies immune-hot tumors in breast cancer and associates with well therapeutic response to immunotherapy.

Breast cancer (BrCa) is a heterogeneous disease, which leads to unsatisfactory prognosis in females worldwide. Previous studies have proved that tumor immune microenvironment (TIME) plays crucial roles in oncogenesis, progression, and therapeutic resistance in Breast cancer. However, biomarkers related to TIME features have not been fully discovered. Proteasome activator complex subunit 2 (PSME2) is a member of proteasome activator subunit gene family, which is critical to protein degradation mediated by the proteasome. In the current research, we comprehensively analyzed the expression and immuno-correlations of Proteasome activator complex subunit 2 in Breast cancer. Proteasome activator complex subunit 2 was significantly upregulated in tumor tissues but associated with well prognosis. In addition, Proteasome activator complex subunit 2 was overexpressed in HER2-positive Breast cancer but not related to other clinicopathological features. Interestingly, Proteasome activator complex subunit 2 was positively related to immune-related processes and identified immuno-hot TIME in Breast cancer. Specifically, Proteasome activator complex subunit 2 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), immune checkpoints, and tumor mutation burden (TMB) levels. Moreover, the positive correlation between Proteasome activator complex subunit 2 and PD-L1 expression was confirmed in a tissue microarray (TMA) cohort. Furthermore, in an immunotherapy cohort of Breast cancer, patients with pathological complete response (pCR) expressed higher Proteasome activator complex subunit 2 compared with those with non-pathological complete response. In conclusion, Proteasome activator complex subunit 2 is upregulated in tumor tissues and correlated with the immuno-hot tumor immune microenvironment, which can be a novel biomarker for the recognition of tumor immune microenvironment features and immunotherapeutic response in Breast cancer.

Progress of CD47 immune checkpoint blockade agents in anticancer therapy: a hematotoxic perspective.

CD47, a transmembrane protein, acts as a "do not eat me" signal that is overexpressed in many tumor cell types, thereby forming a signaling axis with its ligand signal regulatory protein alpha (SIRPα) and enabling the tumor cells to escape from macrophage-mediated phagocytosis. Several clinical trials with CD47 targeting agents are underway and have achieved impressive results preliminarily. However, hematotoxicity (particularly anemia) has emerged as the most common side effect that cannot be neglected. In the development of CD47 targeting agents, various methods have been used to mitigate this toxicity. In this review, we summarized five strategies used to alleviate CD47 blockade-induced hematotoxicity, as follows: change in the mode of administration; dual targeting bispecific antibodies of CD47; CD47 antibodies/SIRPα fusion proteins with negligible red blood cell binding; anti-SIRPα antibodies; and glutaminyl-peptide cyclotransferase like inhibitors. With these strategies, the development of CD47 targeting agents can be improved.

Anticancer Effects of Ginsenoside Rh2: A Systematic Review.

BACKGROUND: As one of the effective pharmacological constituents of Ginseng Radix et Rhizoma, ginsenoside Rh2 (Rh2) exerts a remarkable anticancer effect on various cancer cell lines in vitro and strongly inhibits tumor growth in vivo without severe toxicity. OBJECTIVE: This article reviewed existing evidence supporting the anticancer effects of Rh2 to classify and conclude previous and current knowledge on the mechanisms and therapeutic effects of Rh2, as well as to promote the clinical application of this natural product. CONCLUSION: This article reviewed the anticancer efficacies and mechanisms of Rh2, including the induction of cell cycle arrest and programmed cell death, repression of metastasis, alleviation of drug resistance, and regulation of the immune system. Finally, this paper discussed the research and application prospects of Rh2.

Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma.

Phosphoinositide-3 kinase alpha (PI3Kα) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3Kα inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome-wide gain-of-function screening with a CRISPR-SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full-length EZH2 but not methyltransferase-deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient-derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33-mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient-derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2-p21-RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.

The development of small-molecule inhibitors targeting CD47.

Immunotherapy has become an indispensable part of cancer treatment. A pivotal phagocytosis checkpoint, named cluster of differentiation 47 (CD47), which functions as 'don't eat me' signal to protect cells from phagocytosis upon interaction with signal regulatory protein alpha (SIRPα) on macrophages, has recently attracted much attention. Numerous antibodies targeting the CD47/SIRPα axis have shown encouraging efficacy in clinical trials. Meanwhile, studies on small-molecule inhibitors that interfere with CD47/SIRPα interaction or regulate CD47 expression are also in full swing. In this review, we summarize the small-molecule inhibitors interrupting the binding of CD47/SIRPα and regulating CD47 at the transcriptional, translational, and post-translational modification (PTM) levels. We provide perspectives and strategies for targeting the CD47/SIRPα phagocytosis checkpoint.

Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model.

AIMS: Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models. METHODS: The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment. KEY FINDINGS: Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid ß-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.

Antibiotics modulate neoadjuvant therapy efficiency in patients with breast cancer: a pilot analysis.

Mounting evidence suggests that microbiota dysbiosis caused by antibiotic administration is a risk factor for cancer, but few research reports focus on the relationships between antibiotics and chemotherapy efficiency. We evaluated the influence of antibiotic administration on neoadjuvant therapy efficacy in patients with breast cancer (BC) in the present study. BC patients were stratified into two groups: antibiotic-treated and control based on antibiotic administration within 30 days after neoadjuvant therapy initiation. Disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and the Cox proportional hazards model was used for multivariate analyses. The pathologic complete response rate of the control group was significantly higher than that of the antibiotic-treated group (29.09% vs. 10.20%, p = 0.017). Further univariate analysis with Kaplan-Meier calculations demonstrated that antibiotic administration was strongly linked with both reduced DFS (p = 0.04) at significant statistical levels and OS (p = 0.088) at borderline statistical levels. Antibiotic administration was identified as a significant independent prognostic factor for DFS [hazard ratio (HR) 3.026, 95%, confidence interval (CI) 1.314-6.969, p = 0.009] and OS (HR 2.836, 95% CI 1.016-7.858, p = 0.047) by Cox proportional hazards model analysis. Antibiotics that initiated reduced efficiency of chemotherapy were more noticeable in the HER2-positive subgroup for both DFS (HR 5.51, 95% CI 1.77-17.2, p = 0.003) and OS (HR 7.0395% CI 1.94-25.53, p = 0.003), as well as in the T3-4 subgroup for both DFS (HR 20.36, 95% CI 2.41-172.07, p = 0.006) and OS (HR 13.45, 95% CI 1.39-130.08, p = 0.025) by stratified analysis. Antibiotic administration might be associated with reduced efficacy of neoadjuvant therapy and poor prognosis in BC patients. As a preliminary study, our research made preparations for further understanding and large-scale analyses of the impact of antibiotics on the efficacy of neoadjuvant therapy.

Bioactive platycodins from Platycodonis Radix: Phytochemistry, pharmacological activities, toxicology and pharmacokinetics.

Platycodonis Radix, the root of Platycodon grandiflorum (Jacq.) A. DC., is a well-known edible herbal medicine. It is a common vegetable used for the preparation of side dish, kimchi, dessert, and tea. Besides, it has been used to treat respiratory disease including cough, excessive phlegm, and sore throat for a long history. In the past decades, the bioactive components and the pharmacological activities of Platycodonis Radix have been widely investigated. Thereinto, platycodins, the oleanane-type triterpenoid saponins were demonstrated to be the main bioactive components in Platycodonis Radix, and more than 70 platycodins have been identified up to date. This paper mainly reviewed the phytochemistry, pharmacological activities (apophlegmatic, anti-tussive, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, immunomodulatory, cardiovascular protective, and hepatoprotective activities, etc.), toxicology and pharmacokinetics of platycodins isolated from Platycodonis Radix, aiming to promote further investigation on therapeutic potential of these platycodins.

Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus.

The mammalian target of rapamycin (mTOR) pathway converges diverse environmental cues to support the lung cancer growth and survival. However, the mTOR-targeted mono-therapy does not achieve expected therapeutic effect. Here, we revealed that fangchinoline (FCL), an active alkaloid that purified from the traditional Chinese medicine Stephania tetrandra S. Moore, enhanced the anti-lung cancer effect of mTOR inhibitor everolimus (EVE). The combination of EVE and FCL was effective to activate Notch 3, and subsequently evoked its downstream target c-MYC. The blockage of Notch 3 signal by the molecular inhibitor of γ-secretase or siRNA of Notch 3 reduced the c-MYC expression and attenuated the combinational efficacy of EVE and FCL on cell apoptosis and proliferation. Moreover, the c-MYC could bind to the C/EBP homologous protein (CHOP) promoter and facilitate CHOP transcription. The conditional genetic deletion of CHOP reduced the apoptosis on lung cancer cells to the same degree as blockage of Notch 3/c-MYC axis, providing further evidence for that the Notch 3/c-MYC axis regulates the transcription of CHOP and finally induces apoptosis upon co-treatment of FCL and EVE in lung cancer cells. Overall, our findings, to the best of our knowledge, firstly link CHOP to Notch 3/c-MYC axis-dependent apoptosis and provide the Notch 3/c-MYC/CHOP activation as a promising strategy for mTOR-targeted combination therapy in lung cancer treatment.

A Dose-Escalating Pilot Study (NCT03017404) of Pegylated Liposomal Doxorubicin and Cyclophosphamide, Followed by Docetaxel Administration as a Neoadjuvant Chemotherapy Regimen in Patients with Locally Advanced Breast Cancer.

BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) has a comparable efficacy but a distinct toxicological profile compared with free doxorubicin. The use of PEG-LD and cyclophosphamide followed by docetaxel regimen as neoadjuvant chemotherapy has not been well established. OBJECTIVES: We aimed to assess the maximum tolerated dose (MTD) and toxicity of this regimen in patients with locally advanced breast cancer. METHODS: A total of 19 patients were enrolled in this trial. In the initial treatment plan, patients were given PEG-LD at 35, 40, 45, or 50 mg/m2 on day 1 during the first four cycles, and cyclophosphamide was administered at a dose of 600 mg/m2. During the last four cycles, docetaxel was administered at 75 mg/m2 on day 1 of a 21-day scheme. RESULTS: The MTD was 40 mg/m2 PEG-LD and 600 mg/m2 cyclophosphamide administered on day 1 of a 21-day cycle. Dose-limiting toxicity, grade 3 hand-foot syndrome, was observed in one patient during level 2 and three patients during level 3. Other side effects included neutropenia, anemia, stomatitis, rash, nausea/vomiting, alopecia, transaminase elevation, and cardiotoxicity. The pathological complete response rate was 21.1%. CONCLUSIONS: Our study demonstrated that combination of 40 mg/m2 PEG-LD and 600 mg/m2 cyclophosphamide, followed by 75 mg/m2 docetaxel on day 1 of a 21-day scheme, was an efficacious and well-tolerated neoadjuvant regimen for patients with locally advanced breast cancer.