Glutathione-Responsive and Hydrogen Sulfide Self-Generating Nanocages Based on Self-Weaving Technology To Optimize Cancer Immunotherapy.

As an ideal drug carrier, it should possess high drug loading and encapsulation efficiency and precise drug targeting release. Herein, we utilized a template-guided self-weaving technology of phase-separated silk fibroin (SF) in reverse microemulsion (RME) to fabricate a kind of hyaluronic acid (HA) coated SF nanocage (HA-gNCs) for drug delivery of cancer immunotherapy. Due to the hollow structure, HA-gNCs were capable of simultaneous encapsulation of the anti-inflammatory drug betamethasone phosphate (BetP) and the immune checkpoint blockade (ICB) agent PD-L1 antibody (αPD-L1) efficiently. Another point worth noting was that the thiocarbonate cross-linkers used to strengthen the SF shell of HA-gNCs could be quickly broken by overexpressed glutathione (GSH) to reach responsive drug release inside tumor tissues accompanied by hydrogen sulfide (H2S) production in one step. The synergistic effect of released BetP and generated H2S guaranteed chronological modulation of the immunosuppressive tumor microenvironment (ITME) to amplify the therapeutic effect of αPD-L1 for the growth, metastasis, and recurrence of tumors. This study highlighted the exceptional prospect of HA-gNCs as a self-assistance platform for cancer drug delivery.

Non-Pore Dependent and MMP-9 Responsive Gelatin/Silk Fibroin Composite Microparticles as Universal Delivery Platform for Inhaled Treatment of Lung Cancer.

Developing a drug delivery platform that possesses universal drug loading capacity to meet various requirements of cancer treatment is a challenging yet interesting task. Herein, a self-assembled gelatin/silk fibroin composite (GSC) particle based drug delivery system is developed via microphase separation followed by desolvation process. Thanks to its preassembled microphase stage, this GSC system is suitable for varying types of drugs. The desolvation process fix drugs inside GSC rapidly and densify the GSC structure, thereby achieving efficient drug loading and providing comprehensive protection for loaded drugs. Actually, the size of this brand-new non-pore dependent drug delivery system can be easily adjusted from 100 nm to 20 µm to fit different scenarios. This work selects GSC with 3 µm diameter as the universal inhaled drug delivery platform, which shows an excellent transmucosal penetration and lung retention ability. Additionally, the MMP-9 sensitive degradation property of GSC enhances the targeted efficiency of drugs and reduces side effects. Intestinally, GSC can self-amplify the regulation of innate immunity to reverse the cancerous microenvironment into an antitumor niche, significantly improving the therapeutic effect of drugs. This study of GSC universal drug platform provides a new direction to develop the next-generation of drug delivery system for lung cancer.

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer.

The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals in tumor cells are able to avoid various tumor tolerance mechanisms by alleviating the intracellular hypoxia environment. Herein we reported a nanoreactor Cu2-xSe that enabled the conversion of Cu elements between Cu+ and Cu2+ for the generation of O2 and the consumption of intracellular GSH content. Furthermore, to enhance the catalytic and ferroptosis-inducing activities of the nanoreactors, the ferroptosis agonist Erastin was loaded on the ZIF-8 coating on the surface of Cu2-xSe to up-regulate the expression of NOX4 protein, increase the intracellular H2O2 content, catalyze the Cu+ to produce O2 and activate ferroptosis. In addition, the nanoreactors were simultaneously surface functionalized with PEG polymer and folic acid molecules, which ensured the in vivo blood circulation and tumor-specific uptake. In vitro and in vivo experiments demonstrated that the functionalized self-supplying nanoreactors can amplify the ability to generate O2 and consume intracellular GSH via the interconversion of Cu elements Cu+ and Cu2+, and impair the GPX4/GSH pathway and HIF-1α protein expression. At the same time, by alleviating the intracellular hypoxia environment, the expression of miR301, a gene in the secreted exosomes was decreased, which ultimately affected the phenotype polarization of TAMs and increased the content of IFN γ secreted by CD8+ T cells, which further promoted the ferroptosis induced by Erastin-loaded nanoreactors. This combined therapeutic strategy of activating the tumor immune response and ferroptosis via self-supplying nanoreactors provides a potential strategy for clinical application.

[Retracted] Long non­coding RNA PRNCR1 exerts oncogenic effects in tongue squamous cell carcinoma in vitro and in vivo by sponging microRNA­944 and thereby increasing HOXB5 expression.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the flow cytometric data shown in Fig. 4I were strikingly similar to data appearing in different form in another article by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused [International Journal of Molecular Medicine 46: 119­130, 2020; DOI: 10.3892/ijmm.2020.4581].

Widespread Metastasis to the Stomach 10 Years After Primary Breast Cancer: A case report and review of the literature.

RATIONALE: Breast cancer is a common malignant tumor. The most common metastatic sites of breast cancer are the bone, brain, liver and lung, and gastrointestinal metastases are rare. Considering that the median time interval from the initial breast cancer diagnosis to stomach metastasis is 77.5 months, gastrointestinal metastases are rarely observed 10 years after primary breast cancer. PATIENT CONCERNS: Here, we present a 63-year-old female with unusual endoscopy results that revealed scattered polyps and mucosal infiltration throughout the stomach, which were later confirmed to be metastatic lobular carcinoma of the breast that had been surgically removed 10 years earlier. DIAGNOSIS: The patient was diagnosed with gastric metastases of breast cancer by immunohistochemistry. INTERVENTIONS: The patient underwent endocrine therapy with palbociclib and tamoxifen. OUTCOMES: After 1 year of endocrine therapy, the symptoms of upper abdominal discomfort and fatigue were relieved and a new gastroscopy revealed there had been no significant progression of the gastric metastasis. According to the Response Evaluation Criteria in Solid Tumors (RECIST), the patient reached a state of stable disease. LESSONS: Gastric metastases of breast cancer are rare in the clinical setting. However, considering the possibility of gastric metastases from breast cancer and performing an upper endoscopy are crucial for patients who present with any subtle gastric symptoms and have a past medical history of breast cancer, even if the breast cancer occurred more than 10 years ago.

Small bowel racemose hemangioma complicated with obstruction and chronic anemia: A case report and review of literature.

BACKGROUND: Gastrointestinal hemangiomas are rare benign tumors. According to the size of the affected vessels, hemangiomas are histologically classified into cavernous, capillary, or mixed-type tumors, with the cavernous type being the most common and racemose hemangiomas being very rare in the clinic. Melena of uncertain origin and anemia are the main clinical manifestations, and other presentations are rare. Due to the rarity of gastrointestinal hemangiomas and lack of specific manifestations and diagnostic methods, preoperative diagnoses are often delayed or incorrect. CASE SUMMARY: We report a 5-year-old girl who presented with abdominal pain, nausea, and vomiting for a duration of 10 h. The laboratory studies showed prominent anemia. Computed tomography and contrast-enhanced computed tomography of the abdomen revealed a small bowel obstruction caused by a giant abdominal mass. Segmental resection of the ileal lesions was performed through surgery, and the final pathology results revealed a diagnosis of racemose hemangioma complicated by a small bowel obstruction and simultaneous chronic anemia. CONCLUSION: The current report will increase the understanding of the diagnosis and treatment of gastrointestinal hemangiomas and provide a review of the related literature.

Long non­coding RNA PRNCR1 exerts oncogenic effects in tongue squamous cell carcinoma in vitro and in vivo by sponging microRNA­944 and thereby increasing HOXB5 expression.

A long non­coding RNA (lncRNA) called prostate cancer­associated non­coding RNA 1 (PRNCR1) serves crucial roles in the aggressive phenotypes of colorectal cancer and non­small cell lung cancer. However, there is little research on the expression profile, clinical value and detailed functions of PRNCR1 in tongue squamous cell carcinoma (TSCC). The aim of the present study was to determine PRNCR1 expression in TSCC and to examine the involvement of PRNCR1 in TSCC progression. The molecular mechanisms behind the oncogenic effects of PRNCR1 in TSCC cells were also investigated. PRNCR1 was revealed to be upregulated in TSCC tumors and cell lines. The high PRNCR1 expression showed a significant correlation with tumor size, clinical stage, lymph node metastasis, and shorter overall survival times among patients with TSCC. A PRNCR1­knockdown reduced TSCC cell proliferation, migration and invasion, and increased apoptosis in vitro. Additionally, the PRNCR1­knockdown slowed down in vivo tumor growth of TSCC cells. With regards to the mechanism, PRNCR1 acted as a competing endogenous RNA on microRNA­944 (miR­944) in TSCC cells, and the effects of the PRNCR1­knockdown were reversed by an miR­944­knockdown. HOXB5 was validated as a direct target gene of miR­944 in TSCC cells, and HOXB5 expression was found to be positively regulated by PRNCR1. Furthermore, resumption of HOXB5 expression reversed the tumor­suppressive actions of miR­944 in TSCC cells. In conclusion, PRNCR1 acts as an oncogenic lncRNA in TSCC through the upregulation of HOXB5 by sponging miR­944, thereby indicating a potential therapeutic target in TSCC.

In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study.

Aims: Plaque erosion is a significant substrate of acute coronary thrombosis. This study sought to determine in vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: A prospective series of 822 STEMI patients underwent pre-intervention optical coherence tomography. Using established diagnostic criteria, 209 had plaque erosion (25.4%) and 564 had plaque rupture (68.6%). Plaque erosion was more frequent in women <50 years when compared with those ≥50 years of age (P = 0.009). There was a similar, but less striking, trend in men (P = 0.011). Patients with plaque erosion were more frequently current smokers but had fewer other coronary risk factors (dyslipidaemia, hypertension, chronic kidney disease, and diabetes mellitus) than those with plaque rupture. There was a preponderance of plaque erosion in the left anterior descending artery (LAD; 61.2%), whereas plaque rupture was more equally distributed in both the LAD (47.0%) and right coronary artery (43.3%). Despite the similar spatial distribution of erosions and ruptures over the lengths of the coronary arteries, plaque erosion occurred more frequently near a bifurcation (P < 0.001). In the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion. Nearby bifurcation and current smoking were especially notable in men, while age <50 years was most predictive in women. Conclusions: Plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients, and gender-specific role of risk factors in plaque erosion should be considered.

Lentiviral Vector Mediated Claudin1 Silencing Inhibits Epithelial to Mesenchymal Transition in Breast Cancer Cells.

Breast cancer has a high incidence and mortality rate worldwide. Several viral vectors including lentiviral, adenoviral and adeno-associated viral vectors have been used in gene therapy for various forms of human cancer, and have shown promising effects in controlling tumor development. Claudin1 (CLDN1) is a member of the tetraspan transmembrane protein family that plays a major role in tight junctions and is associated with tumor metastasis. However, the role of CLDN1 in breast cancer is largely unexplored. In this study, we tested the therapeutic potential of silencing CLDN1 expression in two breast cancer (MDA-MB-231 and MCF7) cell lines using lentiviral vector mediated RNA interference. We found that a CLDN1 short hairpin (shRNA) construct efficiently silenced CLDN1 expression in both breast cancer cell lines, and CLDN1 knockdown resulted in reduced cell proliferation, survival, migration and invasion. Furthermore, silencing CLDN1 inhibited epithelial to mesenchymal transition (EMT) by upregulating the epithelial cell marker, E-cadherin, and downregulating mesenchymal markers, smooth muscle cell alpha-actin (SMA) and Snai2. Our data demonstrated that lentiviral vector mediated CLDN1 RNA interference has great potential in breast cancer gene therapy by inhibiting EMT and controlling tumor cell growth.

miR-203 Functions as a Tumor Suppressor by Inhibiting Epithelial to Mesenchymal Transition in Ovarian Cancer.

OBJECTIVE: Ovarian cancer is a gynecological malignancy that has a high mortality rate in women due to metastatic progression and recurrence. miRNAs are small, endogenous, noncoding RNAs that function as tumor suppressors or oncogenes in various human cancers by selectively suppressing the expression of target genes. The objective of this study is to investigate the role of miR-203 in ovarian cancer. METHODS: miR-203 was expressed in ovarian cancer SKOV3 and OVCAR3 cells using lentiviral vector and cell proliferation, migration, invasion were examined using MTT, transwell and Matrigel assays, respectively. Tumor growth was examined using Xenograft mouse model. RESULTS: miR-203 expression was downregulated, whereas expression of its target gene Snai2 was upregulated in human ovarian serous carcinoma tissue as compared to normal ovaries. In addition, high miR-203 expression was associated with long-term survival rate of ovarian cancer patients. miR-203 overexpression inhibited cell proliferation, migration, and invasion of SKOV3 and OVCAR3 ovarian cancer cells. Furthermore, miR-203 overexpression inhibited the epithelial to mesenchymal transition (EMT) in ovarian cancer cells. Silencing Snai2 with lentiviral short hairpin (sh) RNA mimics miR-203-mediated inhibition of EMT and tumor cell invasion. Xenografts of miR-203-overexpressing ovarian cancer cells in immunodeficient mice exhibited a significantly reduced tumor growth. CONCLUSION: miR-203 functions as a tumor suppressor by down regulating Snai2 in ovarian cancer.

Doxycycline inducible Krüppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells.

Ovarian cancer presents therapeutic challenges due to its typically late detection, aggressive metastasis, and therapeutic resistance. The transcription factor Krüppel-like factor 4 (KLF4) has been implicated in human cancers as a tumor suppressor or oncogene, although its role depends greatly on the cellular context. The role of KLF4 in ovarian cancer has not been elucidated in mechanistic detail. In this study, we investigated the role of KLF4 in ovarian cancer cells by transducing the ovarian cancer cell lines SKOV3 and OVCAR3 with a doxycycline-inducible KLF4 lentiviral vector. Overexpression of KLF4 reduced cell proliferation, migration, and invasion. The epithelial cell marker gene E-cadherin was significantly upregulated, whereas the mesenchymal cell marker genes vimentin, twist1 and snail2 (slug) were downregulated in both KLF4-expressing SKOV3 and OVCAR3 cells. KLF4 inhibited the transforming growth factor ß (TGFß)-induced epithelial to mesenchymal transition (EMT) in ovarian cancer cells. Taken together, our data demonstrate that KLF4 functions as a tumor suppressor gene in ovarian cancer cells by inhibiting TGFß-induced EMT.

[Ad-TFPI gene transfer attenuates intimal proliferation in rabbit carotid arteries after balloon injury].

OBJECTIVE: To investigate the in vivo gene expression of adenovirus-mediated human tissue factor pathway inhibitor (hTFPI) and its inhibition effects on intimal proliferation in rabbit carotid arteries after balloon injury. METHODS: Rabbits underwent carotid artery balloon injuries were treated with Ad-TFPI (n = 25), Ad-LacZ (n = 25) or PBS (n = 10), respectively. Sham operated rabbits (n = 10) serve as normal controls. The expressions of human TFPI at mRNA and protein levels were detected by RT-PCR and ELISA respectively on the 3rd, 7th, 10th, 14th, 28th day after operation. Intimal proliferation was detected by angiograms and morphometric analysis. RESULTS: TFPI mRNA and protein expressions were detected at 3 days and peaked at the 10th and 14th day after TFPI gene transfer. The expressions were still detectable on the 28th day. There was no TFPI expression in Ad-LacZ group. The carotid angiogram results indicated that the minimal lumen diameter in TFPI group was significantly larger and the lumina stenosis percentage was significantly lower in TFPI group compared those in Ad-LacZ and PBS groups (all P < 0.05). The morphometric analysis showed that the intimal area, the ratio of the intimal/media area, the lumina stenosis percentage in TFPI group were all significantly reduced compared with those in Ad-LacZ and PBS groups (all P < 0.01). CONCLUSIONS: The TFPI gene could be effectively transferred by adenovirus vector to injured carotid arteries and transferred Ad-TFPI could significantly attenuate intimal proliferation in balloon injured carotid arteries in rabbits.

[Clinical application of spiral 3-D CT reconstruction for maxillary impacted teeth].

PURPOSE: To evaluate the clinical usefulness of spiral 3-D CT reconstruction for maxillary impacted teeth. METHODS: Spiral CT was performed in 47 patients whose maxillary impacted teeth couldn't be judged clearly through the panoramic radiograph and occlusal film. 3-D reconstruction, including MIP (maximum intensity projection) and MPR (multiplanar reconstructions) was made to display the impacted teeth's shape, location and its relationship with adjacent teeth. RESULTS: There were 67 maxillary impacted teeth in 47 patients. Spiral 3-D CT could clearly demonstrate the dental image including crown, root, neck and root bifurcation, and 3-D imaging could clearly display the maxilla anatomy and the dental structure. CONCLUSION: Spiral CT 3-D reconstruction is a useful technique to display three-dimensional configuration of teeth.Three dimensional reconstruction is an accurate and effective method to localize impacted teeth before orthodontic treatment.