Atomically dispersed nanozyme-based synergistic mild photothermal/nanocatalytic therapy for eradicating multidrug-resistant bacteria and accelerating infected wound healing.

Constructing a synergistic multiple-modal antibacterial platform for multi-drug-resistant (MDR) bacterial eradication and effective treatment of infected wounds remains an important and challenging goal. Herein, we developed a multifunctional Cu/Mn dual single-atom nanozyme (Cu/Mn-DSAzymes)-based synergistic mild photothermal/nanocatalytic-therapy for a MDR bacterium-infected wound. Cu/Mn-DSAzymes with collaborative effects exhibit remarkable dual CAT-like and OXD-like enzyme activities and could efficiently catalyze cascade enzymatic reactions with a low level of H2O2 as an initial reactant to produce reparative O2 and lethal ˙O2-. Moreover, a black N-doped carbon nanosheet supports of Cu/Mn-DSAzymes show superior NIR-II-triggered photothermal performance, endowing them with photothermal-enhanced dual enzyme catalysis. In addition, such enhanced dual enzyme catalysis likely improves the susceptibility and lethality of photothermal effects on MDR bacteria. In vitro and in vivo studies demonstrate that Cu/Mn-DSAzyme-mediated synergistic nanocatalytic and photothermal effects possess dramatic antibacterial outcomes against MDR bacteria and evidently reduced inflammation at wound sites. Moreover, the combined photothermal effect and O2 release mediated by Cu/Mn-DSAzymes promotes macrophage polarization to reparative M2 phenotype, collagen deposition, and angiogenesis, considerably accelerating wound healing. Therefore, Cu/Mn-DSAzyme-based synergetic dual-modal antibacterial therapy is a promising strategy for MDR bacterium-infected wound treatment, owing to their excellent antibacterial ability and significant tissue remodeling effects.

Analysis of odor compounds in Lee Kum Kee brand oyster sauce and oyster enzymatic hydrolysate: Comparison and relationship.

Oyster sauce (OS) is a highly processed oyster product. However, the significant price difference between OS and fresh oysters raises a question: Does authentic OS truly contain components from oysters or oyster enzymatic hydrolysates (OEH)? Therefore, the odor compounds of Lee Kum Kee oyster sauce (LKK), 4 OEHs, and 6 other seafood enzymatic hydrolysates (SEHs) were analyzed by using solid-phase microextraction and gas chromatography-olfactometry-mass spectrometry technology (SPME-GC-O-MS). The results of multivariate statistical analysis demonstrated the effective discrimination between LKK and OEHs from other SEHs. According to the VIP value and the differences in the composition of odor compounds among different samples, 15 essential odor compounds were screened out, which could distinguish whether the samples contained OEHs. Among them, acetic acid, 2-pentylfuran, 2-ethyl furan, 2-methylbutanal, and nonanal were only detected in LKK and OEHs, which further indicated the existence of OEH in LKK.

Constructing multifunctional Cu Single-Atom nanozyme for synergistic nanocatalytic Therapy-Mediated Multidrug-Resistant bacteria infected wound healing.

Developing an effective strategy to combat multi-drug-resistant (MDR) bacteria and promote wound healing without overuse of antibiotics remains an important and challenging goal. Herein, we established a synergistic reactive oxygen species (ROS) and reactive nitrogen species (RNS)-mediated nanocatalytic therapy, which was consisted of a multifunctional Cu single-atom nanozyme loaded with the l-arginine (l-Arg@Cu-SAzymes) and a low level of hydrogen peroxide (H2O2) as a trigger. l-Arg@Cu-SAzymes can possess excellent dual enzyme-like activities: catalase (CAT)-like activity that decompose H2O2 into O2, and subsequent oxidase (OXD)-like activity that convert O2 to cytotoxic superoxide anion radical (•O2-). Meanwhile, l-Arg@Cu-SAzymes can also be triggered by H2O2 to release nitric oxide (NO), which can continue to react with •O2- to generate more lethal peroxynitrite (ONOO-). Collectively, the synergistic ROS and RNS mediated by l-Arg@Cu-SAzymes endow the treatment system with an outstanding antibacterial ability against MDR bacteria and reduce the inflammation at the wound site. Furthermore, l-Arg@Cu-SAzymes-mediated NO and O2 release promote the cell proliferation, collagen synthesis, and the angiogenesis, as well as facilitate macrophage polarization to reparative M2 phenotype, thereby accelerating wound closure and tissue remodeling. Therefore, l-Arg@Cu-SAzymes-based synergistic nanocatalytic therapy can be regarded as a promising strategy for MDR bacterial infected wounds treatment, owing to their potent antibacterial efficacy and enhanced tissue remodeling effects.

Identification of cervical cancer stem cells using single-cell transcriptomes of normal cervix, cervical premalignant lesions, and cervical cancer.

BACKGROUND: Cervical cancer is the fourth leading cause of mortality among gynecological malignancies. However, the identification of cervical cancer stem cells remains unclear. METHODS: We performed single-cell mRNA sequencing on ∼122,400 cells from 20 cervical biopsies, including 5 healthy controls, 4 high-grade intraepithelial neoplasias, 5 microinvasive carcinomas of the cervix, and 6 invasive cervical squamous carcinomas. Bioinformatic results were validated by multiplex immunohistochemistry (mIHC) in cervical cancer tissue microarrays (TMA) (n = 85). FINDINGS: We identified cervical cancer stem cells and highlighted the functional changes in cervical stem cells during malignant transformation. The original non-malignant stem cell properties (characterized by high proliferation) gradually diminished, whereas the tumor stem cell properties (characterized by epithelial-mesenchymal transformation and invasion) were enhanced. The mIHC results of our TMA cohort confirmed the existence of stem-like cells and indicated that cluster correlated with neoplastic recurrence. Subsequently, we investigated malignant and immune cell heterogeneity in the cervical multicellular ecosystem across different disease stages. We observed global upregulation of interferon responses in the cervical microenvironment during lesion progression. INTERPRETATION: Our results provide more insights into cervical premalignant and malignant lesion microenvironments. FUNDING: This research was supported by the Guangdong Provincial Natural Science Foundation of China (2023A1515010382), Grant 2021YFC2700603 from the National Key Research & Development Program of China and the Hubei Provincial Natural Science Foundation of China (2022CFB174 and 2022CFB893).

Efficacy of immune checkpoint inhibitor monotherapy or combined with other small molecule-targeted agents in ovarian cancer.

Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.

Developing Single-Atomic Manganese Nanozymes for Synergistic Mild Photothermal/Multienzymatic Therapy.

Synergistic mild photothermal/nanozyme therapy with outstanding hyperthermia performance and excellent multienzyme properties is highly needed for osteosarcoma treatment. Herein, we have developed efficient single-atom nanozymes (SANs) consisting of Mn sites atomically dispersed on nitrogen-doped carbon nanosheets (denoted as Mn-SANs) for synergistic mild photothermal/multienzymatic therapy against osteosarcoma. Benefiting from their black N-doped carbon nanosheet matrices, Mn-SANs showed an excellent NIR-II-triggered photothermal effect. On the other hand, Mn-SANs with atomically dispersed Mn sites have outstanding multienzyme activities. Mn-SANs can catalyze endogenous H2O2 in osteosarcoma into O2 by catalase (CAT)-like activity, which can effectively ease osteosarcoma hypoxia and trigger the oxidase (OXD)-like catalysis that converts O2 to the cytotoxic superoxide anion radical (•O2-). At the same time, Mn-SANs can also mimic glutathione oxidase (GSHOx) to effectively consume the antioxidant glutathione (GSH) in osteosarcoma and inhibit intracellular glutathione peroxidase 4 (GPX4) expression. Such intratumoral •O2- production, GSH depletion, and GPX4 inactivation mediated by Mn-SANs can create a large accumulation of lipid peroxides (LPO) and •O2-, leading to oxidative stress and disrupting the redox homeostasis in osteosarcoma cells, which can ultimately induce osteosarcoma cell death. More importantly, heat shock proteins (HSPs) can be significantly destroyed via Mn-SAN-mediated plentiful LPO and •O2- generation, thus effectively impairing osteosarcoma cells resistant to mild photothermal therapy. Overall, through the cooperative effect of chemical processes (boosting •O2-, consuming GSH, and enhancing LPO) and biological processes (inactivating GPX4 and hindering HSPs), collaborative mild photothermal/multienzymatic therapy mediated by Mn-SANs is a promising strategy for efficient osteosarcoma treatment.

Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study).

Background: This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC). Methods: In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40-60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40-60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety. Results: Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39-32.87]. The median PFS was 9.03 months (95% CI, 6.50-11.56) in the AS group and 5.07 months (95% CI, 4.33-5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37-0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group. Conclusion: Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities. Trial registration: Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.

Efficacy and safety of low-dose apatinib plus S-1 versus regorafenib and fruquintinib for refractory metastatic colorectal cancer: a retrospective cohort study.

Background: At present, regorafenib and fruquintinib are the standard regimens for refractory metastatic colorectal cancer patients in China, but both options have limited efficacy. The aim of this study was to investigate the efficacy and safety of low-dose apatinib plus S-1 compared with regorafenib and fruquintinib in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies. Methods: The records of 114 patients with refractory mCRC in our center from April 2016 to September 2020 were retrospectively reviewed. Among these patients, 43 received apatinib 250 mg/day combined with S-1, 36 received regorafenib starting at 80 mg/day with weekly escalation, and 35 received fruquintinib 5 mg/day orally. Patients received radiographic examination every 1.5-2 months during the treatment period, progression-free survival time and overall survival time were analyzed and recorded. Results: The baseline clinical characteristics of the patients were broadly similar among the three groups. The median progression-free survival (mPFS) was 3.9 months [95% confidence interval (CI): 2.5-5.3] in the apatinib plus S-1 group, 3.1 months (95% CI: 1.9-4.2) in the fruquintinib group, and 2.4 months (95% CI: 2.1-2.7) in the regorafenib group, the mPFS of apatinib plus S-1 was significantly longer than that of regorafenib (HR =0.49, P=0.003) and fruquintinib (HR =0.60, P=0.048). The median overall survival (OS) was 8.2 months (95% CI: 5.4-11.0) in the apatinib plus S-1 group, 7.8 months (95% CI: 5.3-10.3) in the fruquintinib group, and 7.5 months (95% CI: 4.2-10.7) in the regorafenib group, which was comparable among the 3 groups. There was no statistical difference in disease control rate (DCR) among the three groups. Patients in the apatinib plus S-1 group had a higher incidence of hematological toxicity including anemia (62.8%), neutropenia (30.2%), and thrombocytopenia (39.5%), and the hand-foot skin reaction (58.3%) was more prevalent in the regorafenib group, while the adverse reaction of hypertension (45.7%) in the fruquintinib group was very significant. Conclusions: Low-dose apatinib plus S-1 prolonged PFS compared with regorafenib and fruquintinib, and is a potential alternative regimen for the treatment of refractory mCRC with tolerable and controlled toxicity.

PD-1/PD-L1 Inhibitors Monotherapy for the Treatment of Endometrial Cancer: Meta-Analysis and Systematic Review.

PURPOSE: The efficacy of programmed cell death protein 1(PD-1)/Programmed cell death 1 ligand 1 (PD-L1) inhibitors for endometrial cancer remain controversial, and guidelines are inconsistent on which are preferred therapies for advanced disease, or who develop metastases and recurrence. Therefore, we aimed to estimate the efficacy and safety of PD-1/PD-L1 inhibitors in endometrial cancer on a more complete database by adding multiple randomized trials. METHODS: A systematic and comprehensive search was carried out in PD-1/PD-L1 inhibitors monotherapy. RESULTS: The ORR of PD-1/PDL-1 inhibitors was 29%, and subgroup analysis showed that the pooled ORR of the proficient mismatch repair (pMMR) group was 4% and which was 45% of the deficient mismatch repair (dMMR) group. The DCR of PD-1/PD-L1 inhibitors was 48%, through subgroup analysis, we found that the DCR of the pMMR group was 21% and which was 58% of the dMMR group. The proportion of patients occurring overall adverse events was 65% and grade three or higher adverse events was 14%. The proficient mismatch repair (pMMR) group and the deficient mismatch repair (dMMR) group showed different results. CONCLUSION: PD-1/PD-L1 inhibitors had shown little success in the pMMR population and better efficacy in the dMMR population.

Nanocarbon Framework-Supported Ultrafine Mo2C@MoOx Nanoclusters for Photothermal-Enhanced Tumor-Specific Tandem Catalysis Therapy.

Recent advances in the synthesis of multifunctional nanomaterials create new opportunities for the rational design of multimodal chemodynamic therapy (CDT) agents. Precisely tailoring the nanostructure and composition of CDT nanoagents for maximum efficacy remains a challenge. Herein, we report the successful synthesis of nanocarbon framework-supported ultrafine Mo2C@MoOx nanoclusters (C/Mo2C@MoOx) via a pyrolysis of a Mo/ZIF-8 MOF precursor at 900 °C followed by mild surface oxidation. The developed C/Mo2C@MoOx composite demonstrated outstanding performance in photothermal-enhanced tumor-specific tandem catalysis therapy. Specifically, C/Mo2C@MoOx efficiently catalyzed the conversion of endogenous H2O2 to cytotoxic 1O2 via a Russell mechanism, while also converting the O2 byproduct to cytotoxic ·O2- via an oxidase-like mechanism. A high dispersion of active Mo5+ sites in the exposed MoOx shell enhanced the reactive oxygen species (ROS)-generating efficiency of C/Mo2C@MoOx. Moreover, the Mo2C core in the ultrafine Mo2C@MoOx nanoclusters allowed NIR-II (1064 nm)-driven photothermal heating, which significantly boosted the CDT process through photothermal effects. Additionally, the CDT process relied on a redox cycle involving Mo5+/Mo6+ species, which could be sustained by glutathione (GSH) consumption. Given these advantages, C/Mo2C@MoOx demonstrated remarkable synergistic therapeutic efficacy for cancer treatment (both in vitro and in vivo) through tumor microenvironment-stimulated generation of multiple ROS and NIR-II photothermal activity.

Internet of things-assisted intelligent monitoring model to analyse the physical health condition.

BACKGROUND: Nowadays, smart healthcare minimizes medical facilities costs, ease staff burden, achieve unified control of materials and records, and enhance patients' medical experience. Smart healthcare treatments have critical barriers to improving patient outcomes, reducing the regulatory burden, and promoting the transition from volume to benefit. OBJECTIVE: In this paper, the Internet of Things-assisted Intelligent Monitoring Model (IoT-IMM) has been proposed to improve patient health and maintain health records. METHOD: The advanced IoT sensors can monitor patient health and insert into the patients' bodies. Information collected can be analyzed, aggregated, and mined to predict diseases at an early stage. For that, an enhanced deep learning network using Bayes theorem (EDLN-BT) benefits to obtain and verify various patient health data in a specific aspect, making it easy to supervise the patient's activities. RESULTS: The IoT-IMM-based EDLN-BT results show the smart health care monitoring has undergone substantial growth, improving patient satisfaction for the quality of the healthcare services offered in hospitals and many other healthcare facilities. It helps predict health diseases with increased accuracy, prediction rate with minimal residual error delay, and energy consumption.

Preparation of Elastic and Antibacterial Chitosan-Citric Membranes with High Oxygen Barrier Ability by in Situ Cross-Linking.

Chitosan-citric biomembranes Ch-CA-Gx (x = 0-3) were prepared by a simple cross-linking. The dependence of mechanical property, water-resisting capacity, microstructural characteristic, oxygen barrier ability, and thermal properties of membranes on the content of glycerin was investigated. The results revealed that vacuum drying at 80 °C can lead to low-yield amidation and the Maillard reaction, thus affecting the thermal stability and water resistance of biomembranes. Owing to the ionic cross-linking and amidation, the chitosan-citrate complex showed weaker compatibility when the glycerin content increased, thereby leading to discontinuity of microstructure in the Ch-CA-Gx (x = 1-3) membranes, which was in line with the weaker mechanical properties and water-resisting abilities of membranes, compared to Ch-CA-G0. Chitosan membranes showed interestingly high oxygen barrier capabilities under 40 and 80% relative humidity (RH) conditions, probably attributed to the increased diffusion length arising from the hydrogen-bonding, ionic, and covalent cross-linking. The oxygen transmission rates of Ch-CA-Gx were below 0.1 cm3 m-2 day-1 at 40% RH. The Ch-CA-Gx membranes showed a good elasticity assigned to the reversibly cross-linked structure. The membranes presented strong antibacterial activities against Staphylococcus aureus and Escherichia coli bacteria, probably owing to the citric acids. The results demonstrated that these materials have potential applications as membranes or protecting coatings for food packaging and successful cross-linking by means of amidation, and the Maillard reaction under the condition of vacuum drying can be probably applied as a green and alternative method for the fabrication of mechanically tough and antibacterial membranes, fibers, and gels.

miR-365 inhibits cell invasion and migration of triple negative breast cancer through ADAM10.

PURPOSE: Triple negative breast cancer (TNBC) refers to breast cancer that lacks progesterone receptor (PR), estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). MicroRNA-365 (miR-365), a new-found microRNA, has been reported to possess significant functions in a multitude of human cancers. The purpose of this study was to detect thoroughly the molecular mechanisms of miR-365 that underlie the progress of TNBC. METHODS: The mRNA levels of miR-365 and A Disintegrin and Metalloprotease 10 (ADAM10) were measured by real-time polymerase chain reaction (RT-PCR). Luciferase activity report was applied to verify that ADAM10 was a direct target gene of miR-365. Cell proliferation ability was measured by MTT assay. Transwell assay was utilized to test cell migratory and invasive abilities. RESULT: We found that miR-365 was low-expressed in breast cancer tissues and 5 TNBC cell lines compared with the paracancerous samples and a normal cell line MCF10A. Meanwhile, we discovered that the expression of ADAM10 was higher in the 5 TNBC cell lines than in the normal cell line MCF10A. The proliferation, migration and invasion abilities were suppressed by overexpression of miR-365, whereas they were enhanced by interfering miR-365 in breast cancer. The luciferase reporter assay demonstrated that miR-365 directly targeted ADAM10 through directly binding to the 3'-untranslated region (3'-UTR). And the expression of ADAM10 was reduced by exogenous overexpression of miR-365, while it was increased by transfecting of miR-365 inhibitor in MDA-MB-231 and BT483 cells. Furthermore, re-expression of ADAM10 reversed partial functions of the suppressive roles on cell proliferation, migration and invasion by miR-365 TNBC. CONCLUSIONS: MiR-365 inhibited the proliferation, migration and invasion through directly binding to the 3'-UTR of ADAM10 mRNA in TNBC. It is suggested that miR-365/ADAM10 axis may present a new target for the treatment of breast cancer.

Obese patients have higher risk of breast cancer-related lymphedema than overweight patients after breast cancer: a meta-analysis.

BACKGROUND: Increasing scientific evidences suggest that body weight is a risk factor for breast cancer-related lymphedema (LE) in breast cancer patients, but many existing studies have yielded inconclusive results. This meta-analysis aims to provide a more precise estimation of the effects of body mass index (BMI) on LE in breast cancer patients. METHODS: Two authors searched independently in the main English-language databases, including PubMed, Embase, and Cochrane Central Register of Controlled Trials, and the main Chinese databases, including China National Knowledge Infrastructure and WanFang Data from inception through June 1, 2018 in human. Odds ratios with 95% confidence interval were calculated to evaluate the effect of BMI on LE. RESULTS: Twelve studies were identified with a total of 8,039 breast cancer patients, including 2102 patients who were suffered from LE; therefore, the total incidence of LE was 26.15%.The meta-analysis results reveal that the odds ratios were 1.42 [95% confidence interval (CI), 1.20 to 1.68] for BMI 25-30 kg/m2 versus BMI <25 kg/m2 group, 1.39 (95% CI, 1.21 to 1.60) for BMI ≥30 kg/m2 versus BMI 25-30 kg/m2 group, and 1.84 (95% CI, 1.47 to 2.32) for BMI ≥30 kg/m2 versus BMI <25 kg/m2 group. CONCLUSIONS: Our results will generate awareness of LE, especially obese patients should pay more attention to LE after breast cancer than overweight patients. Thus, it is necessary and meaningful to distinguish obese from overweight patients.

Pulmonary cryptococcosis coexisting with adenocarcinoma: a case report and review of the literature.

BACKGROUND: Pulmonary cryptococcosis is a common fungal infection frequently seen in immunocompromised patients. Owing to its nonspecific clinical and radiographic features, the differential diagnosis with secondary tuberculosis, malignant tumor, and bacterial pneumonia is sometimes difficult. Many case reports have focused on misdiagnosis of pulmonary cryptococcosis as a malignant tumor. But to the best of our knowledge, the coexistence of pulmonary cryptococcosis and malignant tumor is rarely presented. CASE PRESENTATION: A 52-year-old immunocompetent Han Chinese woman was presented to our emergency department complaining of headache and vomiting accompanied by postural changes. She was diagnosed with pulmonary cryptococcosis according to results of laboratory tests, computed tomography, and percutaneous lung biopsy. Owing to the poor therapeutic effects of 6-month fluconazole treatment, she underwent a second percutaneous lung biopsy and was diagnosed with pulmonary cryptococcosis coexisting with adenocarcinoma. Delayed treatment of malignant tumor resulted in lymph node metastasis, higher pathologic stage, and probably poorer prognosis. CONCLUSIONS: Our patient's case serves as a reminder not to misdiagnose pulmonary cryptococcosis coexisting with adenocarcinoma.

Tumor stress-induced phosphoprotein 1 as a prognostic biomarker for breast cancer.

BACKGROUND: Recent studies suggested an important relationship between tumor stress-induced phosphoprotein 1 (STIP1) and cancer. However, the expression of STIP1 in breast cancer tissues and its relationship with clinical characteristics and survival have not been investigated in humans. The aim of our work was to evaluate the association of STIP1 and the prognosis of breast cancer patients. METHODS: The included patients were followed-up by telephone and through a review of their outpatient records. The expression of STIP1 was assessed by immunohistochemistry (IHC). The 5-year recurrence-free survival (RFS) rate and the 5-year overall survival (OS) rate were the prognostic indicators evaluated by the Kaplan-Meier method. Univariate and multivariate analyses employing a Cox regression model were used to calculate hazard ratios (HRs). RESULTS: The rate of high expression of STIP1 was 55.3% (126/228) in breast cancer tissues and 14.9% (34/228) in adjacent normal tissues (χ2=81.495, P<0.001). High expression of STIP1 was associated with tumor size, stage and human epidermal growth factor receptor 2 (HER-2) status. The 5-year RFS rate was 75.4% in the STIP1 high expression group and 87.3% in the STIP1 low expression group (χ2=5.721, P=0.017). The 5-year OS rate was 84.1% in the STIP1 high expression group and 94.1% in the STIP1 low expression group (χ2=5.814, P=0.016). STIP1 was found to be an independent relapse predictor for the adjusted HR is 1.983 (95% CI, 1.031-3.815). CONCLUSIONS: High expression of STIP1 is associated with the poor prognosis of breast cancer patients and HER-2 positive expression. STIP1 may therefore serve as a prognostic biomarker for breast cancer patients.

Effect of Ku80 on the radiosensitization of cisplatin in the cervical carcinoma cell line HeLa.

Cisplatin chemotherapy in combination with radiotherapy is the primary therapeutic strategy for the treatment of cervical cancer; however, the underlying molecular mechanism for cisplatin radiosensitization remains unknown. The aim of the present study was to investigate the effect of Ku80, a DNA double-strand break (DSB) repair protein, on cisplatin radiosensitization in cervical cancer. The pre-established Ku80 suppression cervical cancer cell line HeLa/Ku80-siRNA and the normal HeLa cell line underwent 6 MV X-ray irradiation (6 Gy) individually or in combination with 5 µg/ml cisplatin treatment. Alterations in apoptosis, the cell cycle and γH2AX expression were detected. Following irradiation individually and combined with cisplatin, compared with normal HeLa cells, HeLa/Ku80-siRNAexhibited an increased rate of apoptosis (P<0.05). It was identified that the earlier cisplatin was administered following irradiation, the higher the rate of apoptosis. Cell cycle analysis indicated that, following irradiation combined with cisplatin, the cells were arrested in G1 and S phase rather than in G2/M phase following irradiation alone. Microscopic imaging of immunofluorescence staining and western blotting identified that HeLa/Ku80-siRNA cells exhibited more γH2AX foci remaining following treatment with irradiation and cisplatin, particularly in the group treated with 6 Gy irradiation for 1 h together with 23 h of exposure to cisplatin. Irradiation in combination with cisplatin promoted the apoptosis of HeLa cells in association with the inhibition of Ku80, and it was identified that the earlier cisplatin was administered following irradiation, the more apoptosis was induced. This maybe because irradiation combined with cisplatin is able to arrest cells in G1 and S phase to rapidly repair damaged DNA, and the lack of Ku80 induces the inability to repair DSB, resulting in increased apoptosis. The results of the present study suggest that Ku80 may be a potent molecular target in cisplatin radiosensitization.

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation.

BACKGROUND/AIMS: Triple-negative breast cancer (TNBC) is a high-risk breast cancer phenotype without specific targeted therapy options and is significantly associated with increased local recurrence in patients treated with radiotherapy. CAVEOLIN-1 (CAV-1)-mediated epidermal growth factor receptor (EGFR) nuclear translocation following irradiation promotes DNA repair and thus induces radiation resistance. In this study, we aimed to determine whether knockdown of CAV-1 enhances the radiosensitivity of basal-like TNBC cell lines and to explore the possible mechanisms. METHODS: Western blotting was used to compare protein expression in a panel of breast cancer cell lines. Nuclear accumulation of EGFR as well as DNA repair and damage at multiple time points following irradiation with or without CAV-1 siRNA pretreatment were investigated using western blotting and confocal microscopy. The radiosensitizing effect of CAV-1 siRNA was evaluated using a clonogenic assay. Flowcytometry was performed to analyse cell apoptosis and cell cycle alteration. RESULTS: We found that CAV-1 is over-expressed in basal-like TNBC cell lines and barely expressed in HER-2-positive cells; additionally, we observed that HER-2-positive cell lines are more sensitive to irradiation than basal-like TNBC cells. Our findings revealed that radiation-induced EGFR nuclear translocation was impaired by knockdown of CAV-1. In parallel, radiation-induced elevation of DNA repair proteins was also hampered by pretreatment with CAV-1 siRNA before irradiation. Silencing of CAV-1 also promoted DNA damage 24 h after irradiation. Colony formation assays verified that cells could be radiosensitized after knockdown of CAV-1. Furthermore, G2/M cell cycle arrest and apoptosis enhancement may also contribute to the radiosensitizing effect of CAV-1 siRNA. CONCLUSION: Our results support the hypothesis that CAV-1 knockdown by siRNA causes increased radiosensitivity in basal-like TNBC cells. The mechanisms associated with this effect are reduced DNA repair through delayed CAV-1-associated EGFR nuclear accumulation and induction of G2/M arrest and apoptosis through the combined effects of CAV-1 siRNA and radiation.