Correlation analysis of cofilin-1 with renal prognosis in primary IgA nephropathy.

PURPOSE: The purpose of this study was to investigate the correlation between podocyte related biomarker cofilin-1 and renal function, and explore the value of cofilin-1 in predicting the risk of renal adverse prognosis in IgA nephropathy (IgAN). METHODS: Patients with primary IgAN diagnosed by initial renal biopsy performed in our hospital from January 2019 to February 2022 were included. This study was a prospective cohort study. All IgAN patients were detected the expression of cofilin-1 and other related biomarkers (RhoA, NGAL) in urine by enzyme-linked immunosorbent assay (ELISA) and follow-up at least 6 months. We also collected baseline clinicopathologial data of IgAN. The decreased renal function group was defined as baseline eGFR < 60 ml/min/1.73m2. Logistic and Cox regression model were used to analyze the correlation among cofilin-1 and renal prognosis. RESULTS: 133 IgAN patients were included, with a male-to-female ratio of 1.25:1 and an age of 37.67 ± 13.78 years, as well as an average of eGFR was 71.63 (40.42,109.33) ml/min/1.73m2. 56 patients (42.1%) had decreased renal function at baseline, with the average of eGFR was 34.07 (16.72, 49.21) ml/min/1.73 m2. 12 of which developed to renal adverse prognosis. The average of follow-up time was 22.035 ± 8.992 months. The multivariate regression analysis showed that increased urinary cofilin-1 was an independent risk factor associated with baseline renal function decline and renal adverse prognosis in IgAN patients (P < 0.05). ROC curves showed great efficacy of urinary cofilin-1 levels in diagnosing baseline renal function decline and predicting renal adverse prognosis (the area under the ROC curve was 0.708 and 0.803). CONCLUSION: Cofilin-1 as a novel biomarker of podocyte lesion is closely related to renal function decline in IgAN. Cofilin-1 has certain clinical value in predicting the risk of renal adverse prognosis. Podocyte fusion affects the renal prognosis of IgAN.

Water-Stable Hybrid Lead-Free Perovskite for Negative Temperature Coefficient Thermistors.

Negative temperature coefficient (NTC) thermistors feature higher sensitivities and faster response speeds and thereby have particular applications in many fields. However, current NTC thermistors are mostly based on inorganic ceramic materials, which show obvious drawbacks in material synthesis, property modulation, and flexible film fabrication. Herein, we report, for the first time, the promising application of an inorganic-organic hybrid NTC thermistor. A new lead-free hybrid iodo bismuthate [1,1',1″-(benzene-1,3,5-triyl)tris(3-methyl-1H-imidazol-3-ium)]Bi2I9 [denoted as (Me3TMP)Bi2I9] was synthesized by a "double-free" strategy. (Me3TMP)Bi2I9 features a lead-free binuclear bismuth iodine anion charge compensated by a "classic hydrogen-bond-free" cation. (Me3TMP)Bi2I9 exhibits remarkable stability in water and UV light irradiation and shows the largest temperature sensitivity coefficient among all reported NTC materials. Theoretical calculation and detailed structural analysis disclose that the seriously distorted (BiI6) octahedra are responsible for the intriguing NTC effect for (Me3TMP)Bi2I9.

Comparison of 2 dynamic conformal arc plans based on high-dose rate flattening filter free beams for peripheral lung cancer. / åŸºäºŽå‘¨å›´åž‹è‚ºç™Œé«˜å‰‚é‡çŽ‡æ— å‡æ•´æ»¤è¿‡å™¨æ¨¡å¼ä¸‹çš„2种动态适形弧计划比较.

OBJECTIVES: To compare 2 dynamic conformal arc plans based on the high dose rate flattening filter free (FFF) beams, and to evaluate the dosimetric differences. METHODS: A total of 20 patients with early peripheral non-small cell lung cancer were selected, and 2 dynamic conformal arc plans were designed in the Eclipse 10.0 treatment planning system (TPS). One of them was based on tumor-center (T-DCA), and the other was based on iso-center (Iso-DCA). Both plans were created by using the Truebeam linear accelerator, based on 6 MV FFF photons with a dose rate at 1 400 monitor unit (MU)/min. All patients received the prescribed dose of 4 800 cGy in 4 fractions (1 200 cGy/fraction). Target coverage and organ at risk limits were planned and designed according to the Radiation Therapy Oncology Group (RTOG) Criteria, and were compared between the T-DCA and the Iso-DCA plans. RESULTS: There was no significant difference in the target coverage between the T-DCA and Iso-DCA plans (P>0.05). Conformal index and homogeneity index had no significant differences (both P>0.05), but the percentage of the maximum dose in any direction 2 cm away from the planned target area (D2 cm) and the ratio of the volume wrapped by the isodose line of 50% prescription dose to the volume of the planned target area (R50%) showed significant differences (both P<0.05). The MU of the Iso-DCA plan was increased by 21% compared with that of the T-DCA plan. Except the maximum dose of spinal cord and esophagus, there was no significant difference in the other dosimetric parameters of the organs at risk between the T-DCA and the Iso-DCA plans (all P>0.05). CONCLUSIONS: The dose fall-off of Iso-DCA plan is better than T-DCA plan, but the T-DCA plan is consistently superior in sparing dose to spinal cord and esophagus, and the T-DCA plan has fewer MU.

Plasma levels of von Willebrand factor in type 2 diabetes patients with and without cardiovascular diseases: A meta-analysis.

Chronic vascular complications are the major causes of death and disability of type 2 diabetes mellitus (T2DM) patients. von Willebrand factor (vWF) is involved in pathogenesis of cardiovascular diseases (CVD). Previous studies showed elevated plasma levels of vWF in T2DM patients with CVD, but the association has not been validated. The aim of this meta-analysis was to compare plasma levels of vWF in T2DM patients with and without CVD. We performed a meta-analysis based on published case-control studies of vWF in T2DM patients with and without CVD indexed in PubMed and other databases updated to April 2018. After independently assessing methodological quality and extracting data, 9 eligible studies were obtained including 576 cases and 632 controls. The standard mean difference (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects model. Meta-analysis showed that plasma level of vWF was significantly higher in T2DM patients with CVD than T2DM patients without CVD (SMD = 0.61; 95% CI, 0.32-0.90; P < .00001). Subgroup and sensitivity analyses confirmed the robustness of the results. Plasma levels of vWF are significantly elevated in patients with T2DM complicated by CVD. This study helps further characterize the prognostic value of vWF for cardiovascular complications in T2DM patients.

Prognostic value of plasma von Willebrand factor levels in major adverse cardiovascular events: a systematic review and meta-analysis.

BACKGROUND: Prediction of major adverse cardiovascular events (MACEs) may offer great benefits for patients with coronary artery disease (CAD). Von Willebrand factor (vWF) is stored in endothelial cells and released into blood plasma upon vascular dysfunction. This meta-analysis was performed to evaluate the prognostic value of plasma vWF levels in CAD patients with MACEs. METHODS: A total of 15 studies were included in this meta-analysis through the search in PubMed, Embase and CNKI. Data were collected from 960 patients who had MACEs after CAD and 3224 controls nested without the adverse events. The standard mean difference (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects model. RESULTS: The plasma vWF levels examined at 24 h and 48 h after admission were significantly higher in CAD patients with MACEs than those without. The pooled SMD among the MACEs group and the non-MACEs group was 0.55 (95% CI = 0.30-0.80, P < 0.0001) and 0.70 (95% CI = 0.27-1.13, P = 0.001), respectively. However, no significant difference was found in plasma vWF levels on admission between the two groups. CONCLUSION: Plasma vWF level in CAD patients examined at 24 h and 48 h after admission might be an independent prognostic factor for MACE.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

Natural gambogic acid-tuned self-assembly of nanodrugs towards synergistic chemophototherapy against breast cancer.

Gambogic acid (GA) as a naturally derived chemotherapeutic agent is of increasing interest for antitumor therapy. However, current research mainly focuses on improving the pharmacological properties to overcome the shortcomings in clinical applications or as a synergistic anticancer agent in combination with chemotherapy and chemophototherapy. Yet, the material properties of GA (e.g., self-assembly) are often neglected. Herein, we validated the self-assembly function of GA and its huge potential as a single-component active carrier for synergistic delivery using pyropheophorbide-a (PPa) as a drug model. The results showed that self-assembled GA drives the formation of nano-GA/PPa mainly through noncovalent interactions such as π-π stacking, hydrophobic interactions, and hydrogen bonding. Additionally, although no significant differences in cytotoxicity were found between the individual in vitro chemotherapy and combined chemophototherapy, the as-prepared nano-GA/PPa exhibits remarkably improved water solubility and multiple favorable therapeutic features, leading to a prominent in vivo photochemotherapy efficiency of 89.3% inhibition rate with reduced hepatotoxicity of GA. This work highlights the potential of self-assembled GA as a drug delivery carrier for synergistic biomedical applications.

Multimodal Drug Target Binding Affinity Prediction using Graph Local Substructure.

Predicting the binding affinity of drug target is essential to reduce drug development costs and cycles. Recently, several deep learning-based methods have been proposed to utilize the structural or sequential information of drugs and targets to predict the drug-target binding affinity (DTA). However, methods that rely solely on sequence features do not consider hydrogen atom data, which may result in information loss. Graph-based methods may contain information that is not directly related to the prediction process. Additionally, the lack of structured division can limit the representation of characteristics. To address these issues, we propose a multimodal DTA prediction model using graph local substructures, called MLSDTA. This model comprehensively integrates the graph and sequence modal information from drugs and targets, achieving multimodal fusion through a cross-attention approach for multimodal features. Additionally, adaptive structure aware pooling is applied to generate graphs containing local substructural information. The model also utilizes the DropNode strategy to enhance the distinctions between different molecules. Experiments on two benchmark datasets have shown that MLSDTA outperforms current state-of-the-art models, demonstrating the feasibility of MLSDTA.

A modified U-net with graph representation for dose prediction in esophageal cancer radiotherapy plans.

The manual design of esophageal cancer radiotherapy plan is time-consuming and labor-intensive. Automatic planning (AP) is prevalent nowadays to increase physicists' work efficiency. Because of the intuitiveness of dose distribution in AP evaluation, obtaining reasonable dose prediction provides effective guarantees to generate a satisfactory AP. Existing fully convolutional network-based methods for predicting dose distribution in esophageal cancer radiotherapy plans often capture features in a limited receptive field. Additionally, the correlations between voxel pairs are often ignored. This work modifies the U-net architecture and exploits graph convolution to capture long-range information for dose prediction in esophageal cancer plans. Meanwhile, attention mechanism gets correlations between planning target volume (PTV) and organs at risk, and adaptively learns their feature weights. Finally, a novel loss function that considers features between voxel pairs is used to highlight the predictions. 152 subjects with prescription doses of 50 Gy or 60 Gy are collected in this study. The mean absolute error and standard deviation of conformity index, homogeneity index, and max dose for PTV achieved by the proposed method are 0.036 ± 0.030, 0.036 ± 0.027, and 0.930 ± 1.162, respectively, which outperform other state-of-the-art models. The superior performance demonstrates that our proposed method has great potential for AP generation.

Completion rates and myelosuppression degrees of cancer patients receiving radiotherapy or chemoradiotherapy unchanged regardless of delay duration after Omicron infection.

This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (< 10 days COVID-19 group). SAA, hsCRP, ALT, etc., were used to assess COVID-19 infection. Serum levels of SAA, hsCRP and IL-6 were all raised in two COVID-19-infected groups (SAA < 0.01, hsCRP < 0.01, IL-6 < 0.05), but PCT, ALT, LDH and HBDH levels were only elevated in ≥ 10 days COVID-19 group (PCT = 0.0478, ALT = 0.0022, LDH = 0.0313, HBDH = 0.0077). Moreover, moderate and severe infected cases were higher in ≥ 10 days COVID-19 group than < 10 days COVID-19 group (12/102 vs 5/137, p = 0.0211), but no significance in myelosuppression and completion rates among three groups. Omicron infection led to inflammation, liver and cardiovascular injury on cancer patients, but delay duration of radiotherapy or chemoradiotherapy after infection did not affect the completion rates and myelosuppression of current therapy. Besides, severity of Omicron infection was even worse among cancer patients who received delayed treatment.

RPS15 Coordinates with CtIP to Facilitate Homologous Recombination and Confer Therapeutic Resistance in Breast Cancer.

The repair of DNA double-strand breaks (DSBs) through homologous recombination (HR) is vital for maintaining the stability and integrity of the genome. RNA binding proteins (RBPs) intricately regulate the DNA damage repair process, yet the precise molecular mechanisms underlying their function remain incompletely understood. In this study, we highlight the pivotal role of RPS15, a representative RBP, in homologous recombination repair. Specifically, we demonstrate that RPS15 promotes DNA end resection, a crucial step in homologous recombination. Notably, we identify an interaction between RPS15 and CtIP, a key factor in homologous recombination repair. This interaction is essential for CtIP recruitment to DSB sites, subsequent RPA coating, and RAD51 replacement, all critical steps in efficient homologous recombination repair and conferring resistance to genotoxic treatments. Functionally, suppressing RPS15 expression sensitizes cancer cells to X-ray radiation and enhances the therapeutic synergistic effect of PARP1 inhibitors in breast cancer cells. In summary, our findings reveal that RPS15 promotes DNA end resection to ensure effective homologous recombination repair, suggesting its potential as a therapeutic target in cancer treatment.

Hypothesis paper: GDF15 demonstrated promising potential in Cancer diagnosis and correlated with cardiac biomarkers.

BACKGROUND: Cardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction). METHODS: Analysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG). RESULTS: GDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort. CONCLUSION: GDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Volumetric modulation arc radiotherapy with flattening filter-free beams compared with conventional beams for nasopharyngeal carcinoma: a feasibility study.

There is increasing interest in the clinical use of flattening filter-free (FFF) beams. In this study, we aimed to investigate the dosimetric characteristics of volumetric modulated arc radiotherapy (VMAT) with FFF beams for nasopharyngeal carcinoma (NPC). Ten NPC patients were randomly selected to undergo a RapidArc plan with either FFF beams (RA-FFF) or conventional beams (RA-C). The doses to the planning target volumes (PTVs), organs at risk (OARs), and normal tissues were compared. The technical delivery parameters for RapidArc plans were also assessed to compare the characteristics of FFF and conventional beams. Both techniques delivered adequate doses to PTVs. For PTVs, RA-C delivered lower maximum and mean doses and improved conformity and homogeneity compared with RA-FFF. Both techniques provided similar maximum doses to the optic nerves and lenses. For the brain stem, spinal cord, larynx, parotid glands, oral cavity, and skin, RA-FFF showed significant dose increases compared to RA-C. The dose to normal tissue was lower in RA-FFF. The monitor units (MUs) were (536 ± 46) MU for RA-FFF and (501 ±25) MU for RA-C. The treatment duration did not significantly differ between plans. Although both treatment plans could meet clinical needs, RA-C is dosimetrically superior to RA-FFF for NPC radiotherapy.

Self-assembled-monolayers (SAMs) modified template synthesis and characterization of SrTiO3 nanotube arrays.

A self-assembled-monolayers (SAMs) modified anodic aluminum oxide (AAO) membranes were used to generate crystalline strontium titanate (SrTiO3) nanotube arrays, which have been characterized by means of scanning electron microscopy (SEM), X-ray diffraction (XRD) and transmission electron microscopy (TEM), coupled with electron diffraction analysis. The possible formation mechanism can be explained by the induced nucleation effect of the functional headgroups in the SAMs.

Hydrothermal synthesis of SrTiO3 nanoplates through epitaxial self-assembly of nanocubes.

SrTiO3 nanoplates are obtained by the precipitation of an aqueous gel suspension. The gel suspension is prepared by hydrolysis of a Titanium isopropoxide [Ti(OCH(CH3)2)4] solution with NaOH and the addition of Sr(NO3)2. The amount of additive oleic acid plays a significant role in the formation of pure SrTiO3 phase with specific morphologies. The results of transmission electron microscopy (TEM) and electron diffraction (ED) investigations provide evidences that the oriented aggregation of small nanocubes is the dominant growth mechanism for the formation of the observed SrTiO3 nanoplates. The primary nanocrystals are self-assembled in a highly oriented fashion, producing defective single-crystal particles. The above results show that the directional aggregation process can be controlled by changing the temperature of the suspension as well as by adding organic molecules, by which the SrTiO3 particles can be obtained with a controlled size and shape.

Correction: Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin.

[This corrects the article DOI: 10.18632/oncotarget.2741.].

Downregulation of Epstein-Barr virus-encoded latent membrane protein-1 by arsenic trioxide in nasopharyngeal carcinoma cells.

AIMS AND BACKGROUND: It was documented that nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) and that EBV-encoded latent membrane protein-1 expression (LMP1) plays an important role in the pathogenesis of NPC. In preclinical studies, arsenic trioxide (As2O3) has been identified as a promising anticancer agent for treatment of NPC. The purpose of this study is to investigate if this agent can inhibit the expression of LMP1 and therefore lead to growth inhibition of NPC cells in vitro. METHODS: LMP1-positive NPC cells, HNE1-LMP1, were treated with 3 micromol/L of As2O3 for 96 hours. The LMP1 protein expression and mRNA level in HNE1-LMP1 cells were determined by western blot, confocal immunofluorescence staining and semiquantitative reverse transcriptase reaction (RT-PCR). Apoptosis was determined by light microscopy and the TUNEL method. Alterations in the cell cycle distribution were also investigated by flow cytometry. MTT assay and colony formation assay were used to detect the proliferation of the cells. The LMP1-negative parental cell lines HNE1 and HNE2 were used as control in an attempt to elucidate the role of LMP1 in the anticancer effect of As2O3 on NPC cells. RESULTS: The expression of LMP1 at the protein and mRNA level was reduced after exposure to 3 micromol/L As2O3. This dose of As2O3 significantly induced apoptosis and growth retardation of HNE1-LMP1 cells. In addition, more HNE1-LMP1 cells were induced to G0/G1 and G2/M arrest. The same dose of As2O3 had a moderate effect on HNE1 and HNE2 cells. CONCLUSION: Arsenic trioxide can inhibit LMP1 expression and dictate apoptosis and alterations of cell cycle distribution as well as growth retardation. LMP1-positive NPC cells are more sensitive to As2O3 treatment than LMP1-negative NPC cells.

A dosimetric and treatment efficiency evaluation of stereotactic body radiation therapy for peripheral lung cancer using flattening filter free beams.

To investigate potential dosimetric benefits and treatment efficiency of dynamic conformal arc therapy (DCA), intensity modulated radiation therapy (IMRT), and double partial arcs Rapidarc (RA) techniques in the treatment of early-stage peripheral lung cancer using stereotactic body radiotherapy (SBRT) with flattening filter free (FFF) beams. Twenty early-stage peripheral lung cancer patients were selected. For each patient, DCA, IMRT and RA plans were created to meet Radiation Therapy Oncology Group (RTOG) 0915 objectives with 48 Gy covering 95% of the planning target volume (PTV) in 4 fractions. PTV coverage, organs at risk (OARs) doses, planning time, monitor units (MU) and treatment time were evaluated. RA was significantly better than DCA for PTV coverage. RA provided a lower V32Gy to chest wall and less V20Gy to lung over those of DCA and IMRT. For other OARs, there is no significant difference among all three techniques. DCA plans showed significantly less planning time, shorter treatment time and lower MU number than those of RA and IMRT. RA provides a superior dosimetric benefit to DCA and IMRT in the treatment of early-stage lung cancer using SBRT with FFF beams. Considering the MU number, planning time and treatment efficiency, DCA technique is an effective treatment strategy.

Dosimetric analysis of isocentrically shielded volumetric modulated arc therapy for locally recurrent nasopharyngeal cancer.

This study aimed to investigate the dosimetric characteristics of an isocentrically shielded RapidArc (IS-RA) technique for treatment of locally recurrent nasopharyngeal cancer (lrNPC). In IS-RA, the isocenter was placed at the center of the pre-irradiated brainstem (BS)/spinal cord (SC) and the jaws were set to shield the BS/SC while ensuring the target coverage during the whole gantry rotation. For fifteen patients, the IS-RA plans were compared with the conventional RapidArc (C-RA) regarding target coverage, organ-at-risk (OAR) sparing and monitor units (MUs). The relationship between the dose reduction of BS/SC and some geometric parameters including the angle extended by the target with respect to the axis of BS/SC (Ang_BSSC), the minimum distance between the target and BS/SC (Dist_Min) and the target volume were evaluated. The IS-RA reduced the BS/SC doses by approximately 1-4 Gy on average over the C-RA, with more MUs. The IS-RA demonstrated similar target coverage and sparing of other OARs except for slightly improved sparing of optic structures. More dose reduction in the isocentric region was observed in the cases with larger Ang_BSSC or smaller Dist_Min. Our results indicated that the IS-RA significantly improves the sparing of BS/SC without compromising dosimetric requirements of other involved structures for lrNPC.

Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC.