Chinese physician perception on the treatment of chemotherapy-induced anemia: online cross-section survey study.

BACKGROUND: The management of chemotherapy induced anemia (CIA) remains challenging. The potential risk and benefits in providing patient-centered care need to be balanced; the disease is multifactorial; and the major treatments including red blood cell (RBC) transfusions, erythropoiesis-stimulating agents (ESAs) and intravenous injection (i.v.)iron supplementation have a unique set of strengths and limitations. Also, most previous survey based on the patient data could not reveal the process of evaluation and decision-making for CIA treatment from a physician's perspective. As the comparison of China Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines, the standard of CIA treatment in China will vary from United States and Europe, for example, the initial hemoglobin (Hb) for RBC transfusions. In order to understand the diagnosis, treatment, and unmet medical needs of CIA patients, the China Medical Education Association (CMEA), in conjunction with Cancer Hope Medium, initiated the first national survey of Chinese physicians regarding the diagnosis and treatment of CIA. METHODS: The CMEA sent an online, 12-item questionnaire (via wjx.cn) to physicians across China from September 1, 2022 to October 22, 2022. Two hundred and sixty-five samples were calculated usingsurveyplanet.com. The questionnaire evaluated the impact of anemia on chemotherapy interruption, initial treatment, the target Hb level of CIA in, and the current status of ESAs prescription in clinical practice. Respondents were asked to score their reasons for not using ESAs (including safety issues, drug access in practice or adherence) and the risk options of the current treatment including ESAs, RBC transfusion, and i.v.iron. RESULTS: A total of 331 questionnaires among 5,000 web visits were gathered, covering 247 hospitals in 29 provinces across China, of which 130 (53%) were tier IIIA hospitals, 50 (20%) were tier III B hospitals, 59 (24%) were tier IIA hospitals, and 8 (3%) were tier II B hospitals. The frequency of chemotherapy dose delay/reduction due to anemia was 24% [standard deviation (SD) 49%]. Most responding physicians rated an initial Hb level for ESAs treatment to be 80 g/L, with a favorable Hb level for chemotherapy being 100 g/L (60%), which would not limit treatment availability. The majority (67.6%, n=221) of physicians who responded indicated that they had used ESAs for anemia correction, while the others (32.4%, n=106) reported never using them. CONCLUSIONS: This is the first study in conducting a large-scale survey on the diagnosis and treatment of CIA in China from a physicians' perspective. We found that in China, nearly one-quarter of patients undergoing chemotherapy with concurrent anemia may experience interruption of chemotherapy and that the initiation of anemia treatment is not adequately timed. In treating CIA, most physicians prioritize the completion of chemotherapy via Hb level over treating the symptoms of anemia.

Preparation of the black rice starch-gallic acid complexes by ultrasound treatment: Physicochemical properties, multiscale structure, and in vitro digestibility.

This study aimed to investigate the multiscale structure, physicochemical properties, and in vitro digestibility of black rice starch (BRS) and gallic acid (GA) complexes prepared using varying ultrasound powers. The findings revealed that ultrasonic treatment disrupted BRS granules while enhancing the composite degree with GA. The starch granules enlarged and aggregated into complexes with uneven surfaces. Moreover, the crystallinity of the BRS-GA complexes increased to 22.73 % and formed V6-I-type complexes through non-covalent bonds. The increased short-range ordering of the complexes and nuclear magnetic resonance hydrogen (1H NMR) further indicated that the BRS and GA molecules interacted mainly through non-covalent bonds such as hydrogen bonds. Additionally, ultrasound reduced the viscoelasticity of the complexes while minimizing the mass loss of the complexes at the same temperature. In vitro digestion results demonstrated an increase in resistant starch content up to 37.60 % for the BRS-GA complexes. Therefore, ultrasound contributes to the formation of V-typed complexes of BRS and GA, which proves the feasibility of using ultrasound alone for the preparation of starch and polyphenol complexes while providing a basis for the multiscale structure and digestibility of polyphenol and starch complexes.

Mechanism of interaction between L-theanine and maize starch in ultrasonic field based on DFT calculations: Rheological properties, multi-scale structure and in vitro digestibility.

The digestibility of starch-based foods is receiving increased attention. To date, the full understanding of how including L-theanine (THE) can modify the structural and digestive properties of starch has not been fully achieved. Here, we investigated the multi-scale structure and digestibility of maize starch (MS) regulated by THE in ultrasound field and the molecular interactions. Ultrasound disrupted the structure of starch granules and opened the molecular chains of starch, promoting increased THE binding and producing more low-order or disordered crystal structures. In this case, the aggregation of starch molecules, especially amylose, was reduced, leading to increased mobility of the systems. As a result, the apparent viscosity, G', and G" were significantly decreased, which retarded the starch regeneration. Density functional theory calculations indicated that there were mainly non-covalent interactions between THE and MS, such as hydrogen bonding and van der Waals forces. These interactions were the main factors contributing to the decrease in the short-range ordering, the helical structure, and the enthalpy change (ΔH) of MS. Interestingly, the rapidly digestible starch (RDS) content of THE modified MS (MS-THE-30) decreased by 17.89 %, while the resistant starch increased to 26.65 %. These results provide new strategies for the safe production of resistant starch.

Configurational Entropy Strategy Enhanced Structure Stability Achieves Robust Cathode for Aluminum Batteries.

Rechargeable aluminum batteries (RABs) are an emerging energy storage device owing to the vast Al resources, low cost, and high safety. However, the poor cyclability and inferior reversible capacity of cathode materials have limited the enhancement of RABs performance. Herein, a high configurational entropy strategy is presented to improve the electrochemical properties of RABs for the first time. The high-entropy (Fe, Mn, Ni, Zn, Mg)3 O4 cathode exhibits an ultra-stable cycling ability (109 mAh g-1 after 3000 cycles), high specific capacity (268 mAh g-1 at 0.5 A g-1 ), and rapid ion diffusion. Ex situ characterizations indicate that the operational mechanism of (Fe, Mn, Ni, Zn, Mg)3 O4 cathode is mainly based on the redox process of Fe, Mn, and Ni. Theoretical calculations demonstrate that the oxygen vacancies make a positive contribution to adjusting the distribution of electronic states, which is crucial for enhancing the reaction kinetics at the electrolyte and cathode interface. These findings not only propose a promising cathode material for RABs, but also provide the first elucidation of the operational mechanism and intrinsic information of high-entropy electrodes in multivalent ion batteries.

Exploring the formation mechanism of resistant starch (RS3) prepared from high amylose maize starch by hydrothermal-alkali combined with ultrasonic treatment.

In this study, type III resistant starch (RS3) was prepared from high amylose maize starch (HAMS) using hydrothermal (RS-H), hydrothermal combined ultrasonication (RS-HU), hydrothermal-alkali (RS-HA), and hydrothermal-alkali combined ultrasonication (RS-HAU). The role of the preparation methods and the mechanism of RS3 formation were analyzed by studying the multiscale structure and digestibility of the starch. The SEM, NMR, and GPC results showed that hydrothermal-alkali combined with ultrasonication could destroy the granule structure and α-1,6 glycosidic bond of HAMS and reduce the molecular weight of HAMS from 195.306 kDa to 157.115 kDa. The other methods had a weaker degree of effect on the structure of HAMS, especially hydrothermal and hydrothermal combined ultrasonication. The multiscale structural results showed that the relative crystallinity, short-range orderliness, and thermal stability of RS-HAU were significantly higher compared with native HAMS. In terms of digestion, RS-HAU had the highest RS content of 69.40 %. In summary, HAMS can generate many short-chain amylose due to structural damage, which rearrange to form digestion-resistant crystals. With correlation analysis, we revealed the relationship between the multiscale structure and the RS content, which can be used to guide the preparation of RS3.

Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer.

BACKGROUND: The clinical characteristics and efficacy of human epidermal growth factor receptor-2 (HER-2)-directed agents against HER2 mutations and HER2 fusions in breast cancer are obscure due to their low frequency. METHODS: We conducted a retrospective study in patients with advanced breast cancer harboring HER2 mutations and/or HER2 fusions between January 1, 2017 and January 1, 2021. RESULTS: Among a total of 22 patients, 17 HER2 mutations were detected, including L755S, S310F, R100=, V777L, R897W, T862A, 440-17C > G, H878Y, V842I, 73 + 9G > C, T278fs, E1069K, L755P, 226-11C > T, 574 + 12C>T, L114V and P128L. The majority of patients had ductal carcinoma, which mostly coexisted with HER2 amplification/overexpression. The median progression-free survival (PFS) of the 22 patients was 6.9 months (95% CI: 4.7, 9.1) in the first-line setting. The median PFS of patients who received first-line trastuzumab-based regimens was significantly longer than that of patients who received a first-line tyrosine kinase inhibitor (TKI) (10.8 months [95% CI: 2.9, 18.7] vs. 1.9 months [95% CI: 0.8, 3.0], p < 0.005). A total of 14 patients were treated with anti-HER2 antibody-drug conjugate (ADC), among whom the median treatment line of first-time of administration of anti-HER2 ADC was 4.5 (range, 1-10). Anti-HER2 ADC reached an objective response rate (ORR) of 42.9%, a disease control rate (DCR) of 85.7% and a median PFS of 7.3 months (95% CI: 4.4-10.1) from the first-time of administration. CONCLUSION: Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.

Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.

BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.

DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling.

Rationale: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that is the leading cause of cancer-related mortality worldwide. However, genetic alterations and mechanisms underlying HCC development remain unclear. Methods: Tissue specimens were used to evaluate the expression of DEAD-Box 56 (DDX56) to determine its prognostic value. Colony formation, CCK8, and EdU-labelling assays were performed to assess the effects of DDX56 on HCC proliferation. The in vivo role of DDX56 was evaluated using mouse orthotopic liver xenograft and subcutaneous xenograft tumor models. Dual-luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were performed to examine the effect of DDX56 on the MIST1 promoter. Results: DDX56 expression in HCC tissues was elevated and this increase was strongly correlated with poor prognoses for HCC patients. Functionally, DDX56 promoted HCC cell proliferation both in vitro and in vivo, while mechanistically interacting with MECOM to promote HCC proliferation by mono-methylating H3K9 (H3K9me1) on the MIST1 promoter, leading to enhanced MIST1 transcription and subsequent regulation of the PTEN/AKT signaling pathway, which promotes HCC proliferation. More importantly, the PTEN agonist, Oroxin B (OB), blocked the DDX56-mediated PTEN-AKT signaling pathway, suggesting that treating HCC patients with OB may be beneficial as a therapeutic intervention. Furthermore, we observed that ZEB1 bound to DDX56 and transcriptionally activated DDX56, leading to HCC tumorigenesis. Conclusions: Our results indicated that the ZEB1-DDX56-MIST1 axis played a vital role in sustaining the malignant progression of HCC and identified DDX56 as a potential therapeutic target in HCC tumorigenesis.

Protein corona-driven nanovaccines improve antigen intracellular release and immunotherapy efficacy.

During vaccine delivery in vivo, the vaccine carrier dynamically adsorbs the surrounding proteins or biomacromolecules to form a protein corona layer, which determines the physiological and therapeutic responses of the vaccine. Although the importance of the protein corona effect in drug delivery is widely accepted, understanding of the rational use of the protein corona to improve antigen controlled release is still sparse. Here, we constructed a protein corona-driven nanovaccine (PCNV), which has the dual effects of resisting the protein corona-induced antigen extracellular release and promoting protein corona-triggered antigen cytosolic release under reductive conditions. Specifically, the nanovaccine was formulated via the assembly of fluorinated dendrigraft-poly-lysine and cleavable antigen-CpG conjugate. Before entering antigen-presenting cells (APCs), the anchoring effect of CpG was used to avoid the dissociation of antigens from the carrier even under the protein corona effect. While nanovaccine enters the APCs, the intracellular reducing conditions can induce a break in the disulfide bond between CpG and antigen. Notably, at the same time, the intracellular protein corona effect triggers antigen release from the carrier and achieves efficient antigen presentation. In addition, the PCNV produced a significant prophylactic and therapeutic antitumor response in the mouse model. Therefore, the rational use of the protein corona effect provides an effective strategy for vaccine delivery.

Engineering mannosylated pickering emulsions for the targeted delivery of multicomponent vaccines.

While research on cancer vaccines has made great strides in the field of immunotherapy, the targeted delivery of multiple effective components (rational-tailored antigens and adjuvants) remains a challenge. Here, we utilized the unique hierarchical structures of Pickering emulsions (particles, oil core, and water-oil interface) to develop mannosylated (M) Pickering emulsions (PE) that target antigen presenting cells and synergistically deliver antigenic peptides and the TLR9 agonist CpG (C) as an enhanced cancer vaccine (MPE-C). We chemically linked mannose residues to PLGA/PLAG-PEG nanoparticles and produced a dense array of mannose on the nanopatterned surface of Pickering emulsions, allowing for increased cellular targeting. Together with the inherent deformability of the oily core, MPE-C increased the droplet-cellular contact area and provoked the cellular recognition of mannose and CpG for enhanced immune activation. We found that MPE-C attracted a large number of APCs to the local site of administration, evidently increasing cellular uptake and activation. Additionally, we observed increased antigen-specific cellular immune responses, with potent anti-tumor effects against both E.G7-OVA and B16-MUCI tumors. Furthermore, MPE-C combined with PD-1 antibodies produced a significant tumor regression, resulting in synergistic increases in anti-tumor effects. Thus, through the strategic loading of mannose, antigens, and CpG, Pickering emulsions could serve as a targeted delivery platform for enhanced multicomponent cancer vaccines.

First-in-human HER2-targeted Bispecific Antibody KN026 for the Treatment of Patients with HER2-positive Metastatic Breast Cancer: Results from a Phase I Study.

PURPOSE: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a "3+3" dose escalation rule followed by dose expansion. RESULTS: Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2-8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSIONS: KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

Efficacy and safety of mitoxantrone hydrochloride liposome injection in Chinese patients with advanced breast cancer: a randomized, open-label, active-controlled, single-center, phase II clinical trial.

PURPOSE: This trial aimed to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection (Lipo-MIT) in advanced breast cancer (ABC). METHODS: In this randomized, open-label, active-controlled, single-center, phase II clinical trial, eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety outcomes. RESULTS: Sixty patients were randomized to receive Lipo-MIT or MIT. The ORR was 13.3% (95% confidence interval (CI): 3.8-30.7%) for Lipo-MIT and 6.7% (95% CI: 0.8-22.1%) for MIT. The DCR was 50% (95% CI: 31.3-68.7%) with Lipo-MIT vs. 30% (95% CI: 14.7-49.4%) with MIT. The median PFS was 1.92 months (95% CI: 1.75-3.61) for Lipo-MIT and 1.85 months (95% CI: 1.75-2.02) for MIT. The most common toxicity was myelosuppression. Lipo-MIT resulted in an incidence of 86.7% of leukopenia and 80.0% of neutropenia, which was marginally superior to MIT (96.7% and 96.7%, respectively). Lipo-MIT showed a lower incidence of cardiovascular events (13.3% vs. 20.0%) and increased cardiac troponin T (3.3% vs. 36.7%); but higher incidence of anemia (76.7% vs. 46.7%), skin hyperpigmentation (66.7% vs. 3.3%), and fever (23.3% vs. 10.0%) than MIT. Conclusions The clinical benefit parameters of Lipo-MIT and MIT were comparable. Lipo-MIT provided a different toxicity profile, which might be associated with the altered distribution of the drug. Additional study is needed to elucidate the potential benefit of Lipo-MIT in ABC. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (No. NCT02596373) on Nov 4, 2015.

Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis.

BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin's lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression. METHODS: Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH. RESULTS: We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues. CONCLUSIONS: Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy.

Exosomal annexin A6 induces gemcitabine resistance by inhibiting ubiquitination and degradation of EGFR in triple-negative breast cancer.

Exosomes are carriers of intercellular information that regulate the tumor microenvironment, and they have an essential role in drug resistance through various mechanisms such as transporting RNA molecules and proteins. Nevertheless, their effects on gemcitabine resistance in triple-negative breast cancer (TNBC) are unclear. In the present study, we examined the effects of exosomes on TNBC cell viability, colony formation, apoptosis, and annexin A6 (ANXA6)/EGFR expression. We addressed their roles in gemcitabine resistance and the underlying mechanism. Our results revealed that exosomes derived from resistant cancer cells improved cell viability and colony formation and inhibited apoptosis in sensitive cancer cells. The underlying mechanism included the transfer of exosomal ANXA6 from resistant cancer cells to sensitive cancer cells. Isobaric peptide labeling-liquid chromatography-tandem mass spectrometry and western blotting revealed that ANXA6 was upregulated in resistant cancer cells and their derived exosomes. Sensitive cancer cells exhibited resistance with increased viability and colony formation and decreased apoptosis when ANXA6 was stably overexpressed. On the contrary, knockdown ANXA6 restored the sensitivity of cells to gemcitabine. Co-immunoprecipitation expression and GST pulldown assay demonstrated that exosomal ANXA6 and EGFR could interact with each other and exosomal ANXA6 was associated with the suppression of EGFR ubiquitination and downregulation. While adding lapatinib reversed gemcitabine resistance induced by exosomal ANXA6. Moreover, ANXA6 and EGFR protein expression was correlated in TNBC tissues, and exosomal ANXA6 levels at baseline were lower in patients with highly sensitive TNBC than those with resistant TNBC when treated with first-line gemcitabine-based chemotherapy. In conclusion, resistant cancer cell-derived exosomes induced gemcitabine resistance via exosomal ANXA6, which was associated with the inhibition of EGFR ubiquitination and degradation. Exosomal ANXA6 levels in the serum of patients with TNBC might be predictive of the response to gemcitabine-based chemotherapy.

Engineering the Deformability of Albumin-Stabilized Emulsions for Lymph-Node Vaccine Delivery.

A major challenge in vaccine delivery is to achieve robust lymph-node (LN) accumulation, which can capitalize on concentrated immunocytes and cytokines in LNs to stimulate the onset and persistence of adaptive immune responses. Previous attempts at developing vaccine delivery systems have focused on the sizes, charges, or surface ligands but not on their deformability. In fact, the LN homing of antigen-presenting cells depends on deformability to pass through the cellular gaps. Herein, the deformability of albumin-stabilized emulsions is engineered. Owing to self-adaptive deformability, the droplets (≈330 nm) can attach to and deform between cells and adjust their sizes to pass through the endothelial gaps (20-100 nm), favoring direct LN transfer (intercellular pathway). Additionally, owing to relatively large sizes, some emulsions can be retained at the administration sites for potent antigen uptake and activation of APCs as well as LN-targeted delivery of vaccines (intracellular pathway). Compared with solid particles, the dual LN transfer strategy evidently enhances antigen accumulation and activation of LN drainage, potently stimulates cellular immune responses, and increases the survival rate of tumor-bearing mice. Thus, the deformability of albumin-stabilized droplets may offer an efficient strategy for potent LN targeting and enhanced vaccinations.

An integrated bioinformatics analysis to investigate the targets of miR-133a-1 in breast cancer.

BACKGROUND: The microRNA (miRNA) miR-133a-1 has been identified as a tumor suppressor in breast cancer. However, the underlying mechanisms of miR-133a-1 in breast cancer have not been fully elucidated. This study aimed to explore the targets of miR-133a-1 in breast cancer using an integrated bioinformatics approach. METHODS: Human SKBR3 breast cancer cells were transfected with miR-133a-1 or a miRNA negative control (miRNA-NC) for 48 hours. The RNA-seq sequencing technique was performed to identify the differential expression of genes induced by miR-133a-1 overexpression. Functional enrichment analysis was conducted to determine the target genes and pathways involved in breast cancer. RESULTS: Breast cancer patients with high levels of miR-133a-1 expression commonly showed longer overall survival compared to patients with a low level of miR-133a-1 expression. Using Cuffdiff, we identified 1,216 differentially expressed genes induced by miR-133a-1 overexpression, including 653 upregulated and 563 downregulated genes. MOCS3 was the most upregulated gene and KRT14 was the most downregulated gene. The top 10 pathways related to the differentially expressed genes were identified through Gene Ontology (GO) enrichment analysis. Sex-determining region Y-box 9 (SOX9) demonstrated the highest semantic similarities among the differentially expressed genes. Since SOX9 and CD44 were hub nodes in the protein-protein interaction network, the SOX9 gene may be a target of miR-133a-1 in breast cancer. CONCLUSIONS: This report provides useful insights for understanding the underlying mechanisms in the pathogenesis of breast cancer.

Retracted: Naturally Occurring Sesquiterpene Lactone-Santonin, Exerts Anticancer Effects in Multi-Drug Resistant Breast Cancer Cells by Inducing Mitochondrial Mediated Apoptosis, Caspase Activation, Cell Cycle Arrest, and by Targeting Ras/Raf/MEK/ERK Signaling Pathway.

It is now clear that the photomicrographs in Figure 2 are duplicates of the same image and that Figures 4 and 5 have been 'copied' from a publication "Lupeol triterpene exhibits potent antitumor effects in A427 human lung carcinoma cells via mitochondrial mediated apoptosis, ROS generation, loss of mitochondrial membrane potential and downregulation of m-TOR/PI3Ksol;AKT signalling pathway" by Wei He, Xiang Li, Shuyue Xia, PMID: 30003730. Because the manuscript contains non-credible results and has also breached copyright, this journal is retracting the above publication.

Maintenance chemotherapy is effective in patients with metastatic triple negative breast cancer after first-line platinum-based chemotherapy.

BACKGROUND: Platinum-based chemotherapy (PBCT) has gained an important position as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). We assessed whether maintenance chemotherapy maintenance was superior to observation after first-line PBCT in patients with mTNBC. METHODS: A total of 265 patients with mTNBC who had exhibited non-PD after 4-6 cycles of firstline PBCT at the Fudan University Shanghai Cancer Center from January 2008 to April 2019 were retrospectively analyzed. 107 patients who did not receive additional treatment were defined as the control observation group, and the remaining 158 patients who continued to receive maintenance therapy were defined as the maintenance treatment group. RESULTS: The median progression-free survival (PFS) time in the maintenance group was 9.63 months, which was significantly longer than the PFS time of 7.47 months in the observation group (HR 0.49, 95% CI: 0.37-0.67, P<0.0001). The median overall survival (OS) of the observation group and the maintenance group was 25.37 months and 31.27 months, respectively (HR 0.65, 95% CI: 0.44-0.95, P=0.019). The survival benefit was still present after adjusting baseline characteristics. Moreover, multivariate analyses suggested that maintenance chemotherapy is an independent predictive factor for both PFS and OS. Interaction and stratified analyses showed no difference in the PFS with between the single-drug maintenance strategy, single agent or doublet group and the doublet-drug maintenance group. The most common adverse event in this study was hematologic toxicity. Except for hand-foot syndrome (0 vs. 7.6%, P=0.004), the incidence of other adverse events was not significantly different between the observation and maintenance groups. CONCLUSIONS: After achieving non-PD with the first-line PBCT in mTNBC patients, chemotherapy maintenance may provide OS benefit prior to the era of biologicals.

Lanostane inhibits the proliferation and bone metastasis of human breast cancer cells via inhibition of Rho-associated kinase signaling.

PURPOSE: This study was performed to investigate the effects of lanostane against human breast cancer cells with emphasis on its potential to inhibit cancer cell growth and metastasis along with understanding the underlying molecular mechanism mediating the effects. METHODS: The SK-BR-3 normal breast line and the MB-157 breast cancer cell line were used in this study. MTT of cell growth was used to determine the viability of cells under lanostane treatment. Colony formation assay was used to analyze the clone forming capability of cancer cells when treated with lanostane. DAPI and acridine orange (AO)/ethidium bromide (EB) staining assays were performed for assessing the apoptic cell death. The level of cellular apoptosis was further examined using flow cytometry. Wound healing and transwell assays were performed to determine the migration and invasion of cancer cells. Western blotting was used for determining the concentration of proteins of interest. RESULTS: The lanostane treatment of cancer cells resulted in loss of cell viability. The IC50 value was 15µM and the inhibitory effects were dose-dependent. However, the inhibition of cell proliferation in normal breast cells was comparatively lower. The antiproliferative effects of lanostane were modulated through Bax/Bcl-2 pathway inducing apoptosis of cancer cells. Furthermore, the lanostane rendered cancer cells less motile and reduced their metastasis remarkably. The inhibition of cell metastasis was modulated through Rho-associated kinases (ROCK) signaling pathway which is involved in metastasis of breast cancer to bone tissues. Hence, the results suggested that lanostane inhibited the breast cancer metastasis to bone. CONCLUSION: The results of the present study are suggestive of anticancer effects of lanostene triterpene which exerted its effects by inhibiting cell proliferation and metastasis of breast cancer cells mediated through inactivation of Rho-associated kinase signaling. The study holds promise to provide a lead for exploring the secondary metabolite-based anticancer approach against various human malignancies.

MicroRNA-143 targets MAPK3 to regulate the proliferation and bone metastasis of human breast cancer cells.

MicroRNAs (miRs) have shown tremendous potential to act as therapeutic targets for cancer treatment. In this context, the present study was designed to investigate the potential of miR-143 in the treatment of breast cancer. Results showed that miR-143 to be significantly (P < 0.05) downregulated in breast cancer tissues and cell lines. The miR-143 has inhibitory effect on CAMA-1cell growth which was manifested as significant (P < 0.05) decline in loss of viability of cancer cells. The loss of cell viability was revealed to be due to the induction of apoptotic cell death as evident from acridine orange/ethidium bromide (AO/EB) and 4',6-diamidino-2-phenylindole (DAPI) staining assays. The apoptotic cell percentage was found to be 35.7% in miR-143 mimics transfected in comparison to 6.4% in miR-NC transfected cells. The western blot analysis showed that miR-143 caused enhancement in Bax and suppression in Bcl-2 expression in CAMA-1 cells. The miR-143 also suppressed the bone metastasis of the CAMA-1 cells by suppressing the expression of Jag1 and deactivation of the Rho-signalling pathway. The transwell assays also showed considerable anti-metastatic effects of miR-143 on CAMA-1 cells. Taken together, miR-143 has growth inhibitory anti-metastatic effect on breast cancer and thus may prove beneficial in breast cancer treatment.