Platelet Membrane Coated Cu9S8-SNAP for Targeting NIR-II Mild Photothermal Enhanced Chemodynamic/Gas Therapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and uncommon subtype of breast cancer with a poor prognosis. It is crucial to prioritise the creation of a nanotherapeutic method that is highly selective and actively targeting TNBC. This study explores a new nanosystem, Cu9S8-SNAP@PM (C-S@P), composed of Cu9S8-SNAP coated with a platelet membrane (PM). The purpose of this nanosystem is to cure TNBC using multimodal therapy. The utilisation of PM-coated nanoparticles (NPs) enables active targeting, leading to the efficient accumulation of C-S@P within the tumour. The Cu9S8 component within these NPs serves the potential to exert photothermal therapy (PTT) and chemodynamic therapy (CDT). Simultaneously, the S-Nitroso-N-Acetylvanicillamine (SNAP) component enables nitric oxide (NO) gas therapy (GT). Furthermore, when exposed to NIR-II laser light, Cu9S8 not only increases the temperature of the tumour area for PTT, but also boosts CDT and stimulates the release of NO through thermal reactions to improve the effectiveness of GT. Both in vitro and in vivo experimental results validate that C-S@P exhibits minimal side effects and represents a multifunctional nano-drug targeted at tumors for efficient treatment. This approach promises significant potential for TNBC therapy and broader applications in oncology.

NIR absorptive croconic acid/quercetin/CaO2 nanoplatform for tumor calcium overload therapy combined mild photothermal therapy.

With excellent biocompatibility, stable chemical and optical properties, small organic molecules-based agents have always been a research hotspot in cancer photothermal therapy (PTT). In this work, a novel croconic acid-based molecule (CR) was designed and synthesized as an ideal photothermal agent (PTA), which showed abundant near-infrared (NIR) light absorption, high photothermal conversion ability, and excellent photothermal stability. By loading CR and quercetin (Qu) in CaO2, and coated with DSPE-PEG2000, a multifunctional theranostic nanoparticle (CCQ) was successfully prepared for calcium overloading mitochondrial metabolism inhibition synergetic mild PTT. Upon entering tumor microenvironment, CCQ can produce abundant H2O2 and a large amount of calcium ions, which lead to the imbalance of calcium concentration in the internal environment of tumor cells and induced mitochondrial apoptosis. With the existence of Qu, CCQ can effectively inhibit the expression of heat shock proteins (Hsp) during the PTT process, which weaken the heat resistance of tumors, ablate tumors at lower temperature (~45 °C), and reduce the damage to normal tissues. Guided by photoacoustic imaging (PAI), CCQ showed excellent multimodal therapeutic effect of tumors. This study provided a novel CR organic molecule-based theranostic nanoplatform that can be used to treat tumors via calcium overload therapy synergetic PTT at safe temperatures, which has promising potential for the future clinical cancer treatment.

Long Non-Coding RNA (lncRNA) 91H Confers Tamoxifen Resistance in ER+ Breast Cancer Cells through Inhibiting mTOR Signaling Pathway.

OBJECTIVE: Estrogen receptor-positive (ER+) breast cancers are the most often diagnosed subtype of breast tumors, in which the development of tamoxifen resistance remains a major impediment. The effect of long non-coding RNA (lncRNA) on therapy resistance is beginning to emerge. The lncRNA 91H, a recently identified lncRNA involved in tumorigenesis, is also overexpressed in breast cancer. The purpose of this study was to explore the role of 91H in the biological function and tamoxifen resistance of ER+ breast cancer cells. METHODS: MCF-7 and T47D cells were transfected for 91H silence. CCK-8 assay was performed to examine cell viability and drug sensitivity. Cell cycle and apoptosis were analyzed using flow cytometry. Cell migration capacity was determined by wound healing assay. The protein level was analyzed by Western blotting. RESULTS: MCF-7 and T47D cells with 91H knockdown exhibited lower capacities of cell proliferation and migration. In addition, knockdown of 91H resulted in significantly increased sensitivity to tamoxifen and a higher ratio of apoptosis induced by tamoxifen. Furthermore, the protein level of p-mTOR was notably inhibited through downregulating 91H expression. And the mTOR inhibitor together with tamoxifen presented synergistic effect on the inhibition of cell viability. CONCLUSION: Our study highlights that 91H might serve as a potential target for ER+ breast cancer patients who have acquired tamoxifen resistance.

Engineered Red Blood Cell Membrane-Coating Salidroside/Indocyanine Green Nanovesicles for High-Efficiency Hypoxic Targeting Phototherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) presents special biological behavior and clinicopathological characteristics and leads to a worse prognosis than other types of breast cancer. The development of an effective therapeutic method is significant to improve the survival rate of TNBC cancer patients. In this work, an engineered red blood cell membrane (RBCm)-coating salidroside/indocyanine green nanovesicle (ARISP) is successfully prepared for hypoxic targeting phototherapy of TNBC. Salidroside in ARISP effectively ameliorates hypoxia-induced tumorigenesis by downregulating the expression of hypoxia-inducible factor 1α (HIF-1α), which increases the killing effect of reactive oxygen species on tumor cells during photodynamic therapy (PDT) using the photosensitizer indocyanine green. Besides, ARISP has an anti-LDLR modified RBCm-coating that extends its circulation time in the blood and escapes from immune surveillance and enhances hypoxia-targeted cellular uptake via the overexpressed LDLR receptor in hypoxic tumor sites. Moreover, guided by near-infrared fluorescence imaging and photoacoustic imaging, ARISP can eliminate tumors via high-efficiency phototherapy and inhibit lung and liver metastasis in TNBC models. Cytotoxicity assay of ARISP indicates the excellent biocompatibility with normal cells and tissues. This study provides fulfilling insights into the anticancer mechanism of reducing HIF-1α for enhanced PDT and has a promising therapeutic potential for TNBC treatment.

Carbohydrates based stimulus responsive nanocarriers for cancer-targeted chemotherapy: a review of current practices.

INTRODUCTION: Many nanocarriers have been developed to react physicochemically to exterior stimuli like ultrasonic, light, heat, and magnetic fields, along with various internal stimuli including pH, hypoxia, enzyme, and redox potential. Nanocarriers are capable to respond various stimuli within the cancer cells to enable on-demand drug delivery, activation of bioactive compounds, controlled drug release, and targeting ligands, as well as size, charge, and conformation conversion, enabling sensing and signaling, overcoming multidrug resistance, accurate diagnosis, and precision therapy. AREAS COVERED: Carbohydrates are ubiquitous biomolecules with a high proclivity for supramolecular network formation. Numerous carbohydrate-based nanomaterials have been used in biological solicitations and stimuli-based responses. Particular emphasis has been placed on the utilization of carbohydrate-based NPs and nanogels in various fields including imaging, drug administration, and tissue engineering. Because the assembly process is irreversible, carbohydrate-based systems are excellent ingredients for the development of stimulus-responsive nanocarriers for cancer-targeted chemotherapy. This review aims to summarise current research on carbohydrate-based nanomaterials, with an emphasis on stimuli-sensitive nanocarriers for cancer-targeted chemotherapy. EXPERT OPINION: Carbohydrates-based stimulus-responsive nanomaterials have been proved highly efficient for targeted delivery of anticancer drugs, thus leading to effective chemotherapy with minimum off-target effects.

Metastasis patterns and prognosis of octogenarians with metastatic breast cancer: A large-cohort retrospective study.

BACKGROUND: Breast cancer may differ biologically in patients aged over 80 years. The objective of the current study was to analyze the metastasis patterns and prognosis of elderly patients with metastatic breast cancer (MBC) and compare it to patients of other ages. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to select MBC patients from 2010 to 2015. Chi-squared test was used to compare clinicopathological characteristics among different aged groups. The Kaplan-Meier method and multivariate Cox model were utilized for survival analysis. RESULTS: A total of 10479 MBC patients were included, among which 1036 (9.9%) patients were aged over 80 years. Compared with other aged group, the elderly patients tended to have a higher proportion of HR+/Her2- subtype, white race, lower tumor differentiation, and receive less treatment, including surgery, chemotherapy and radiotherapy (P< 0.001). MBC patients with different age presented with distinctive metastatic patterns. The older patients were more likely to have lung metastasis, but less likely to have bone, brain, liver and multiple sites metastasis than the younger group (P <0.001). The proportion of TNBC subtype increased substantially in the older patients with brain metastasis, compared to the younger and middle-aged group. The old age was demonstrated to significantly associate with worse prognosis of MBC patients. Additionally, our findings also showed that older MBC patients could achieve dramatical overall survival benefit from surgery (HR = 0.58; P <0.001) and chemotherapy (HR = 0.59; P <0.001), but not the radiotherapy (HR = 0.96; P = 0.097). CONCLUSION: The elderly MBC patients presented with distinctive metastatic patterns, clinical characteristics, and prognostic outcomes compared with younger patients. Our findings could assist clinicians in making appropriate therapeutic decision.

Identification of exosomal miR-455-5p and miR-1255a as therapeutic targets for breast cancer.

Accumulated evidence has demonstrated exosomes of cancer cells carry microRNAs (miRNAs) to non-malignant cells to induce metastasis. The present study aimed to identify crucial exosomal miRNAs for breast cancer (BC) using microarray data (GSE83669 and GSE50429) from Gene Expression Omnibus database, including exosomal samples from human BC cells (MCF7, MDA-MB-231) and normal mammary epithelial cell line (MCF10, MCF-10A), as well as original cell samples. Differentially expressed miRNAs (DEMs) were identified using EdgeR package, and mRNA targets were predicted using miRWalk2 database. The target genes were overlapped with BC genes from Comparative Toxicogenomics Database (CTD) to construct BC-related interaction network. Potential functions were analyzed by DAVID. The expression of crucial miRNAs and target genes were confirmed in other microarray datasets or TCGA sequencing data. Their associations with survival and other clinical characteristics were validated by Kaplan-Meier plotter and LinkedOmics database. As a result, 9 and 8 DEMs were identified to be shared in two datasets for exosomal and original cells, respectively. Further comparison showed that miR-455-5p was specifically differentially expressed in exosomes, and miR-1255a was commonly expressed in exosomal and original cells samples. miR-455-5p could interact with CDKN1B to influence cell cycle process and miR-1255a could regulate SMAD4 to participate in TGF-ß signaling pathway. High expressed miR-455-5p (basal-like) and miR-1255a (overall) were associated with poor overall survival, while the high expression of their target genes was associated with excellent overall, recurrence-free or distant metastasis-free survival. In conclusion, the present study preliminarily indicates that exosomal miR-455-5p and miR-1255a may be novel therapeutic targets for BC.

miR-618 Suppresses Metastasis in Gastric Cancer by Downregulating the Expression of TGF-ß2.

Recent studies have demonstrated that microRNAs regulate gene expression and are related to cancer progression. Increasing evidence shows that miR-618 plays an important role in a variety of tumors, including thyroid carcinomas, breast cancer and lymphoma cancer. However, no studies have examined the expression or function of miR-618 in gastric cancer (GC). In this study, we examined the effects and molecular mechanisms of miR-618 in GC. We compared the expression levels of miR-618 in 90 paired GC tissues and adjacent noncancerous tissues. Cell cycle, apoptosis and transwell assays were performed in GC cells with miR-618 mimic or inhibitor in vitro. We first used quantitative PCR(qPCR) to show that miR-618 expression levels were downregulated in GC tissues, which showed statistical significance. Next we used transwell assays to prove that miR-618 suppressed the invasion and migration capacity of GC cells. Furthermore, screening of the miRDB and Target Scan Human databases indicated TGF-ß2 as a downstream target of miR-618. In further research, we identified TGF-ß2 as a target gene of miR-618 by the luciferase reporter assay. Western blot analysis confirmed that TGF-ß2 expression was inversely correlated with miR-618 expression. In situ hybridization showed that miR-618 expression level was downregulated in GC tissues. In conclusion, our findings suggest that miR-618 may function as a tumor suppressor in GC and suppresses metastasis in GC by negatively regulating the transcriptional level of TGF-ß2. Anat Rec, 302:931-940, 2019. © 2019 Wiley Periodicals, Inc.

Metastasis-associated protein 1 (MTA1) in gastric cancer tissues is positively associated with poorer prognosis.

BACKGROUND: The present study examined the clinical significance of metastasis-associated protein 1 (MTA1) in the progression and patient survival of gastric cancer. METHODS: Paraffin-embedded resected tissues of gastric cancer mucosa (n = 436) and adjacent normal mucosa (n = 92) were assessed immunohistochemically for MTA1 protein, and scored according to the percentage of cells positively stained for MTA1 combined with stain intensity. Associations between MTA1 staining scores and clinicopathological factors, including survival time, were evaluated. RESULTS: The staining scores for MTA1 were significantly higher in gastric cancer tissues than in matched normal tissues. MTA1 scores positively correlated with tumor size, depth of invasion, presence of lymph node metastasis, lymphatic involvement, venous invasion, distal metastasis, and advanced clinical staging. Patients with high MTA1 scores in gastric cancer tissues had a significantly lower five-year survival rate compared with patients with low MTA1 scores. The multivariate analysis indicated that MTA1 protein levels in resected gastric cancer tissues, as reflected by immunohistochemical staining, are an independent prognostic index of gastric carcinoma (P < 0.01). CONCLUSION: MTA1 immunopositivity was significantly associated with progression of gastric cancer, and may be helpful in gastric cancer prognosis.

Diagnostic accuracy of CK-19, Galectin-3 and HBME-1 on papillary thyroid carcinoma: a meta-analysis.

The study aimed at evaluating the diagnostic accuracy of cytokeratin 19 (CK-19), Galectin-3 and hector battifora mesothelial antigen-1 (HBME-1) for papillary thyroid carcinoma (PTC). The eligible studies were searched in relevant databases with predefined key searching terms and inclusion criteria. Then, the quality assessment was performed by using Diagnostic Accuracy Studies scoring tool. Following the heterogeneity test, a meta-analysis of pooled several effect size including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) with their 95% confidence intervals (CIs) were conducted by Meta-DiSc software. Next, the summary receiver operating characteristic ROC (SROC) curve was drawn. Total 29 studies with high quality were included in this meta-analysis. The pooled result of CK-19 showed that sensitivity, specificity, PLR, NLR and DOR were 0.816 (95% CI: 0.799-0.832), 0.872 (95% CI: 0.855-0.888), 5.900 (95% CI: 5.193-6.703), 0.205 (95% CI: 0.185-0.228), respectively. For Galectin-3, the pooled sensitivity, specificity, PLR, NLR and DOR were 0.842 (95% CI: 0.825-0.858), 0.833 (95% CI: 0.814-0.851), 5.057 (95% CI: 4.494-5.690), 0.176 (95% CI: 0.154-0.200) and 33.312 (95% CI: 26.403-42.029). For HBME-1, the pooled sensitivity, specificity, PLR, NLR and DOR were 0.928 (95% CI: 0.913-0.941), 0.864 (95% CI: 0.847-0.880), 6.204 (95% CI: 5.498-7.002), 0.082 (95% CI: 0.067-0.102), 57.107 (95% CI: 43.421-75.107), respectively. The area under curve (AUC) value in SROC curve of CK-19, Galectin-3 and HBME-1 were 0.9134 (95% CI: 0.877-0.950), 0.8452 (95% CI: 0.809-0.882) and 0.9047 (95% CI: 0.868-0.941), respectively. Compared with CK-19 and Galectin-3, HBME-1 was a more accurate maker and might be used independently for PTC diagnosis. CK-19 and Galectin-3 might as second-line detection for PTC diagnosis.

Horner's syndrome subsequent to minimally invasive video-assisted thyroidectomy in two patients.

Horner's syndrome (HS), characterized by a combination of ptosis and miosis, is an uncommon complication of thyroid surgery, particularly in minimally invasive thyroid surgery. Two cases of HS were observed secondary to minimally invasive video-assisted thyroidectomy in the Department of Thyroid Breast Surgery of Zhejiang Provincial People's Hospital between August 2012 and July 2014. The two patients developed miosis and ptosis following total thyroidectomy; all symptoms had resolved at 1 and 11 months subsequent to surgery, respectively. HS has currently been reported secondary to numerous types of minimally invasive thyroid procedures. The literature was reviewed to identify cases of this iatrogenic complication secondary to each type of thyroidectomy and the possible injury mechanisms underlying the syndrome were summarized in the present study. In addition, factors that were associated with minimally invasive thyroidectomy, such as the limited endoscopic vision during the procedure, the retraction effect and the occurrence of thermal damage from the use of the harmonic scalpel, were emphasized. The present study concluded that close attention is required during minimally invasive thyroid surgery in order to avoid HS as a complication of the procedure.

The oncoplastic breast surgery with pedicled omental flap harvested by laparoscopy: initial experiences from China.

BACKGROUND: A new technique of oncoplastic breast surgery (OBS) using laparoscopically harvested pedicled omental flap has been developed in the past 10 years. This study aimed to evaluate the feasibility of this technique. METHODS: Twenty-five patients underwent OBS using laparoscopically harvested omental flap. Operative time, blood loss, complications, recurrence, and cosmetic outcomes were prospectively analyzed. RESULTS: Between June 2010 and March 2014, 25 patients were recruited in our study. The surgery was performed successfully in 24 patients. All these patients recovered uneventfully after the surgery. Mean operative time was 310 min, ranging from 205 to 410 min. Mean blood loss was 70 ml, ranging from 20 to 150 ml. Patients were followed up for 32 months on average, ranging from 6 to 51 months. Four patients complained of mild epigastric discomfort. One patient had local recurrence and distant bone and liver metastasis and died 11 months after the surgery. One patient was diagnosed with metastases in the lung, bone, and liver without local recurrence 2 years after surgery. The cosmetic satisfaction rate was 91.7% and 95.8% by surgeon and patients, respectively. CONCLUSION: OBS with laparoscopically harvested omental flap might be a feasible technique with a good cosmetic outcome.

The effect of continuous jejunal interposition on gastrointestinal hormones after distal gastrectomy.

The objective of our study was to determine the effect of continuous jejunal interposition on gastrointestinal hormones after distal gastrectomy, and lay a foundation for surgical management.Distal subtotal gastrectomy experimental model were established on 24 adult Beagle dogs. Digestive tract reconstruction of the dogs was randomly divided into continuous jejunal interposition group, Billroth II anastomosis group and isolated jejunum interposition group. The content of serum gastrin, plasma motilin and cholecystokinin after different digestive tract reconstructions was detected and compared by enzyme-linked immunosorbent assay. In the dogs which received continuous jejunal interposition, postoperative serum gastrin level was significantly lower than before surgery either in fasting or postprandial state (all p<0.05). The serum gastrin level of continuous jejunal interposition group was significantly higher than the other groups in postprandial state (all p<0.05), and was significantly higher than Billroth II -type anastomosis group in fasting state (p<0.05). Furthermore, the postoperative plasma motilin and cholecystokinin levels were significantly higher than before surgery either in fasting or postprandial in dogs received continuous jejunal interposition (all p<0.05). The postoperative plasma motilin level of continuous jejunal interposition group was significantly higher than the other groups in postprandial state (all p<0.05), and was significantly higher than Billroth II -type anastomosis group in fasting state (p<0.05). However, the postoperative cholecystokinin level of continuous jejunal interposition group was significantly lower than the other groups (all p <0.05).Continuous jejunal interposition after distal gastrectomy could maintain the postoperative plasma motilin and serum gastrin in a relatively high level, while cholecystokinin in a low level.

[Laparoscopic versus open wedge resection for gastrointestinal stromal tumors of the stomach: a clinical controlled study].

OBJECTIVE: To compare the surgical outcomes between laparoscopic and open wedge resection for gastrointestinal stromal tumors of the stomach. METHODS: Clinical data of 18 cases undergoing laparoscopic wedge resection from June 2000 to August 2009 at the Zhejiang Provincial People's Hospital were compared with 30 patients treated by open surgery. The perioperative parameters and prognosis data of the two groups were compared. RESULTS: Compared to the open group, laparoscopic group was found with longer operative time, less blood loss, less requirement of postoperative analgesia, earlier resumption of oral intake, earlier return of first flatus, and shorter postoperative hospital stay(all P<0.05). There were no postoperative deaths in both groups. Postoperative complication rate was significantly lower in the laparoscopic group(5.5% vs. 33.3%, P<0.05). The postoperative recurrence rates were 11.8%(2/17) and 10.7%(3/28); the 5-year survival rates were 78% and 63%, respectively, and the difference was not statistically significant(P>0.05). CONCLUSION: Laparoscopic wedge resection is a feasible treatment option for GISTs of the stomach.