Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

Glomuvenous malformation: a clinicopathological analysis of 31 cases / 中华病理学杂志

Objective: To investigate the clinicopathological features of glomuvenous malformation (GVM). Methods: Thirty-one cases of GVM diagnosed at the Henan Provincial People's Hospital from January 2011 to December 2021 were collected. Their clinical and pathological features were analyzed. The expression of relevant markers was examined using immunohistochemistry. The patients were also followed up. Results: There were 16 males and 15 females in this study, with an average age of 11 years (range, 1-52 years). The locations of the disease included 13 cases in the limbs (8 cases in the upper limbs, 5 cases in the lower limbs), 9 cases in the trunks, and 9 cases in the foot (toes or subungual area). Twenty-seven of the cases were solitary and 4 were multifocal. The lesions were characterized by blue-purple papules or plaques on the skin surface, which grew slowly. The lumps became larger and appeared to be conspicuous. Microscopically, GVM mainly involved the dermis and subcutaneous tissue, with an overall ill-defined border. There were scattered or clustered irregular dilated vein-like lumens, with thin walls and various sizes. A single or multiple layers of relatively uniform cubic/glomus cells were present at the abnormal wall, with scattered small nests of the glomus cells. The endothelial cells in the wall of abnormal lumen were flat or absent. Immunohistochemistry showed that glomus cells strongly expressed SMA, h-caldesmon, and collagen IV. Malformed vascular endothelial cells expressed CD31, CD34 and ERG. No postoperative recurrence was found in the 12 cases. Conclusions: GVM is an uncommon type of simple venous malformation in the superficial soft tissue and different from the classical glomus tumor. Morphologically, one or more layers of glomus cells grow around the dilated venous malformation-like lumen, which can be combined with common venous malformations.

Macrophage-targeted nanomedicine for the diagnosis and management of atherosclerosis.

Atherosclerosis is the primary cause of cardiovascular diseases, such as myocardial infarction and stroke, which account for the highest death toll worldwide. Macrophage is the major contributor to atherosclerosis progression, and therefore, macrophage-associated pathological process is considered an extremely important target for the diagnosis and treatment of atherosclerosis. However, the existing clinical strategies still have many bottlenecks and challenges in atherosclerosis's early detection and management. Nanomedicine, using various nanoparticles/nanocarriers for medical purposes, can effectively load therapeutic agents, significantly improve their stability and accurately deliver them to the atherosclerotic plaques. In this review, we summarized the latest progress of the macrophage-targeted nanomedicine in the diagnosis and treatment of atherosclerosis, and their potential applications and clinical benefits are also discussed.

MRI-based radiomics analysis for predicting the EGFR mutation based on thoracic spinal metastases in lung adenocarcinoma patients.

PURPOSE: This study aims to develop and evaluate multi-parametric MRI-based radiomics for preoperative identification of epidermal growth factor receptor (EGFR) mutation, which is important in treatment planning for patients with thoracic spinal metastases from primary lung adenocarcinoma. METHODS: A total of 110 patients were enrolled between January 2016 and March 2019 as a primary cohort. A time-independent validation cohort was conducted containing 52 patients consecutively enrolled from July 2019 to April 2021. The patients were pathologically diagnosed with thoracic spinal metastases from primary lung adenocarcinoma; all underwent T1-weighted (T1W), T2-weighted (T2W), and T2-weighted fat-suppressed (T2FS) MRI scans of the thoracic spinal. Handcrafted and deep learning-based features were extracted and selected from each MRI modality, and used to build the radiomics signature. Various machine learning classifiers were developed and compared. A clinical-radiomics nomogram integrating the combined rad signature and the most important clinical factor was constructed with receiver operating characteristic (ROC), calibration, and decision curves analysis (DCA) to evaluate the prediction performance. RESULTS: The combined radiomics signature derived from the joint of three modalities can effectively classify EGFR mutation and EGFR wild-type patients, with an area under the ROC curve (AUC) of 0.886 (95% confidence interval [CI]: 0.826-0.947, SEN =0.935, SPE =0.688) in the training group and 0.803 (95% CI: 0.682-0.924, SEN = 0.700, SPE = 0.818) in the time-independent validation group. The nomogram incorporating the combined radiomics signature and smoking status achieved the best prediction performance in the training (AUC = 0.888, 95% CI: 0.849-0.958, SEN = 0.839, SPE = 0.792) and time-independent validation (AUC = 0.821, 95% CI: 0.692-0.929, SEN = 0.667, SPE = 0.909) cohorts. The DCA confirmed potential clinical usefulness of our nomogram. CONCLUSION: Our study demonstrated the potential of multi-parametric MRI-based radiomics on preoperatively predicting the EGFR mutation. The proposed nomogram model can be considered as a new biomarker to guide the selection of individual treatment strategies for patients with thoracic spinal metastases from primary lung adenocarcinoma.

Multiparametric MRI-Based Radiomics Approaches for Preoperative Prediction of EGFR Mutation Status in Spinal Bone Metastases in Patients with Lung Adenocarcinoma.

BACKGROUND: Preoperative prediction of epidermal growth factor receptor (EGFR) mutation status in patients with spinal bone metastases (SBM) from primary lung adenocarcinoma is potentially important for treatment decisions. PURPOSE: To develop and validate multiparametric magnetic resonance imaging (MRI)-based radiomics methods for preoperative prediction of EGFR mutation based on MRI of SBM. STUDY TYPE: Retrospective. POPULATION: A total of 97 preoperative patients with lumbar SBM from lung adenocarcinoma (77 in training set and 20 in validation set). FIELD STRENGTH/SEQUENCE: T1-weighted, T2-weighted, and T2-weighted fat-suppressed fast spin echo sequences at 3.0 T. ASSESSMENT: Radiomics handcrafted and deep learning-based features were extracted and selected from each MRI sequence. The abilities of the features to predict EGFR mutation status were analyzed and compared. A radiomics nomogram was constructed integrating the selected features. STATISTICAL TESTS: The Mann-Whitney U test and χ2 test were employed for evaluating associations between clinical characteristics and EGFR mutation status for continuous and discrete variables, respectively. Least absolute shrinkage and selection operator was used for selection of predictive features. Sensitivity (SEN), specificity (SPE), and area under the receiver operating characteristic curve (AUC) were used to evaluate the ability of radiomics models to predict the EGFR mutation. Calibration and decision curve analysis (DCA) were performed to assess and validate nomogram results. RESULTS: The radiomics signature comprised five handcrafted and one deep learning-based features and achieved good performance for predicting EGFR mutation status, with AUCs of 0.891 (95% confidence interval [CI], 0.820-0.962, SEN = 0.913, SPE = 0.710) in the training group and 0.771 (95% CI, 0.551-0.991, SEN = 0.750, SPE = 0.875) in the validation group. DCA confirmed the potential clinical usefulness of the radiomics models. DATA CONCLUSION: Multiparametric MRI-based radiomics is potentially clinical valuable for predicting EGFR mutation status in patients with SBM from lung adenocarcinoma. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: 2.

Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells.

Oridonin (ORI) has been reported as an antiproliferation and apoptosis-inducing natural product in various cancer cells. However, the exact molecular mechanism underlying these effects remains unclear. In the present study, we demonstrated the antiproliferation effect of ORI in HCT116 cells, and analyzed the possible molecular mechanism which mediates this effect. We found that ORI inhibits proliferation, induces cell cycle arrest and apoptosis in HCT116 cells, thus also tumor growth. Mechanically, we found that ORI has no substantial effect on mRNA expression of phosphatase and tensin homologue (PTEN), but increases the total protein level of PTEN and markedly reduces the phosphorylation of PTEN; Exogenous expression of PTEN potentiates the anticancer effect of ORI, while knockdown of PTEN attenuates it. ORI also increases the phosphorylation of p38 MAPK, and p38 MAPK-specific inhibitor reduces the antiproliferation effect ORI in HCT116 cells. Moreover, inhibition of p38 MAPK increases the phosphorylation of PTEN, and reverses ORI-induced decrease of PTEN phosphorylation. Our findings suggested that ORI may be a potential anticancer drug for colon cancer, this effect may be mediated by enhancing the function of PTEN through reducing its phosphorylation, which may be resulted from the ORI-induced activation of p38 MAPK.

Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK.

Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK.

Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice.

AIMS: This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD). METHODS: 3 × Tg-AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. RESULTS: Icariin significantly improved spatial learning and memory retention in 3 × Tg-AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N-acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aß plaque deposition in the cortex and hippocampus of AD mice, and inhibited ß-site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aß1-42 in 3 × Tg-AD primary neurons, modulated the distribution of Aß along the neurites, and protected against mitochondrial fragmentation in 3 × Tg-AD neurons. CONCLUSIONS: Icariin shows neuroprotective effects in 3 × Tg-AD mice and may be a promising multitarget drug in the prevention/protection against AD.

BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer.

Colon cancer is one of the most common malignancies of the digestive system. Although more effective therapeutic strategies have been developed in the last decades, there is still a great clinical need to explore new treatment regimens for colon cancer due to the undesirable prognosis. In the present study, we investigated the anticancer activity of resveratrol (Res) in human colon cancer cells, and the possible mechanism underlying this effect. We employed crystal violet staining, flow cytometry and western blotting to test the antiproliferation- and apoptosis-inducing effects of Res in LoVo cells. A xenograft tumor model was also introduced to confirm the in vivo anticancer effect of Res. Using PCR, western blotting, a recombinant adenovirus and a specific inhibitor of p38 MAPK or bone morphogenetic protein receptor (BMPR) to explore the possible molecular mechanisms. We found that Res markedly inhibited the proliferation and promoted the apoptosis of LoVo cells, and suppressed the in vivo tumor growth of colon cancer. Res substantially upregulated the expression of bone morphogenetic protein 9 (BMP9). Exogenous expression of BMP9 enhanced the anticancer effect of Res in LoVo cells, while BMP9 knockdown partly reduced this activity. Res increased the activation of p38 MAPK, which was enhanced by the exogenous expression of BMP9. The anticancer activity of Res, or Res combined with BMP9, was reduced partly by the p38 MAPK inhibitor. The BMPR inhibitor almost abolished the Res-induced activation of p38 MAPK, and attenuated the antiproliferative effect of Res in the LoVo cells. Our findings strongly suggest that the anticancer effect of Res in human colon cancer cells may be partly mediated by upregulation of BMP9 to activate p38 MAPK in a BMPR-dependent manner.

Solid Pseudopapillary Tumor of the Pancreas in a 50-Year-Old Man: A Case Report and Review of the Literature.

Background: A solid pseudopapillary tumor (SPT) of the pancreas is a rare neoplasm with low malignancy, constituting about 2% of pancreatic tumors, which mainly occurs in young women. Case Presentation: We herein report a case of a small SPT arising from the head of the pancreas in an asymptomatic 50-year-old man. This patient was admitted to our department at Henan Provincial People's Hospital for the evaluation of a pancreatic mass and a pancreatic resection was performed. Histology revealed the lesion to be an SPT of the pancreas, with the characteristic pseudopapilla formation, central degeneration, and capsule formation. The tumor was positive for vimentin, CD10, α1-antichymotrypsin, α1-antitrypsin, ß-catenin, neuron-specific enolase, synaptophysin, and progesterone receptor. Conclusion: We diagnosed an SPT in the patient based on these histological findings and immunophenotype.

Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1α downregulation.

Colon cancer is one of the most common malignancies. Although the current treatment regimes for colon cancer have been well-developed in the past decades, the prognosis remains still undesirable. It is still urgent to explore new treatment strategies for colon cancer. Natural products is one of the most useful sources for anticancer agents, although some of them have serious side-effects. Evodiamine (Evo) is an quinolone alkaloid from the traditional herb medicine Evodia rutaecarpa. In the present study, we investigated the anticancer effect of Evo in human colon cancer cells. We found that Evo exhibits prominent antiproliferation and apoptosis inducing effects in LoVo cells. Evo leads to apparent downregulation of HIF-1α either in vitro or in vivo; exogenous expression of HIF-1α can attenuate the antiproliferation effect of Evo in LoVo cells, while HIF-1α knockdown potentiates this effect greatly. Further analysis indicated that Evo can also inhibit the phosphorylation of Akt1/2/3 and decrease greatly the expression of IGF-1. Thus, our findings strongly suggested that the anticancer effect of Evo in human colon cancer may be partly mediated by downregulating HIF-1α expression, which is initiated by inactivating PI3K/Akt signaling transduction though decreasing the expression of IGF-1 in colon cancer cells. Therefore, Evo may be used alone or in combination as a potential anticancer agent for colon cancer treatment.

The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts.

Mouse embryonic fibroblasts (MEFs) are multi-potent progenitor cells (MPCs), can differentiate into different lineages, such as osteogenic, and adipogenic. PTEN, a tumor suppressor, may be involved in regulating bone development through interacting with COX-2. BMP9, the most potent osteogenic BMPs, can up-regulate COX-2 in MPCs. Whether PTEN is involved in BMP9 induced osteogenic differentiation in MPCs remains unknown. The goal of this investigation is to identify the effect of PTEN on BMP9-induced osteogenic differentiation in MPCs and dissect the possible mechanism underlay this. We found that BMP9 down-regulates PTEN, and PTEN inhibitor (VO) effectively increases different osteogenic markers induced by BMP9 in MEFs. Exogenous expression of PTEN inhibits BMP9 induced ectopic bone formation apparently. Mechanistically, we found that VO can enhance BMP9 induced BMPs/Smads signaling prominently without no substantial effects on cell cycle. Further analysis indicates that VO can promote BMP9-induced expression of COX-2 in MEFs, which can be eliminated by PI3K inhibitor. Additionally, COX-2 knockdown abolishes the effect of VO on BMP9-induced ALP activities in MEFs. Our findings suggest that PTEN plays an important role in regulating BMP9 induced osteogenic differentiation in MPCs, which may be mediated by PTEN/PI3K/Akt signaling to modulate the expression of COX-2.

The PTEN/PI3K/Akt and Wnt/ß-catenin signaling pathways are involved in the inhibitory effect of resveratrol on human colon cancer cell proliferation.

Colon cancer is one of the most common malignancies and the treatments for colon cancer have been developed substantially in the last decades, but there is still a great clinical need to explore new treatment regimens due to the undesirable prognosis. In this investigation, we demonstrated the anti-proliferative and apoptosis-inducing activities of resveratrol (Res) in human colon cancer cells, and the possible mechanisms underlying these effects. We used crystal violet staining, flow cytometry and western blotting to validate the anti-proliferative and apoptosis-inducing effects of Res on HCT116 cells. A xenograft tumor model was used to confirm the anti-proliferative effects of Res. We employed polymerase chain reaction, western blotting, recombinant adenovirus and luciferase reporter assay to explore the possible mechanism(s) of action. We found that Res inhibits significantly the proliferation and promotes apoptosis in HCT116 cells, as well as inhibits the xenograft tumor growth of colon cancer. Res upregulates the expression of phosphatase and tensin homolog (PTEN) and decreases the phosphorylation of Akt1/2. The exogenous expression of PTEN inhibits the PI3K/Akt signal and promotes the anti-proliferative effects of Res in HCT116 cells, while knockdown of PTEN increases PI3K/Akt signal but reduces the anti-proliferative function of Res. The protein and mRNA expression of ß-catenin are all decreased by Res concentration-dependently. Thus, our findings strongly suggest that the anti-proliferative effects of Res in human colon cancer cells may be mediated by regulating separately the PTEN/PI3K/Akt and Wnt/ß-catenin signaling.

Endovascular stenting for symptomatic vertebral artery ostial stenosis:the clinical effect and follow-up study / 中国脑血管病杂志

Objective Toinvestigatetheoperativeeffectandsafetyofendovascularstentingfor thetreatmentofsymptomaticvertebralarteryostialstenosis.Methods Fortypatientswithsymptomatic vertebral artery ostial stenosis and stenosis rate ≥70% were admitted to the Department of Neurology, China-Japan Friendship Hospital from November 2010 to January 2013 were enrolled retrospectively. All patients received endovascular stenting therapy,15 of them were implanted bare metal stents,and 25 were implanted drug eluting stents. The technical successful rate of operation,perioperation complications,and symptom remission rate of the patients were analyzed. At the same time,stroke and death incident as well as the related ischemic symptoms of the stent vascular feeding area in the follow-up period (13 to 36 months)wereobservedandtherestenosisratewasdocumented.Results Atotalof42stentswereimplanted in 40 patients,and the technical success rate was 100. 0%. The preoperative stenosis rate of vertebral artery ostial stenosis was 75% to 99%(mean 85 ± 7%);the postoperative stenosis rate was 0% to 20%(mean 6 ± 4%). There was no perioperative complication. The clinical symptoms of 19 patients disappeared completely,16 were improved significantly within the follow-up period,and the symptom remission rate was 87. 5%. No stent vascular feeding area related stroke and death occurred. Four patients had transient ischemic attack in posterior circulation,13 had restenosis after procedure (10 of them with bare mental stents and 3 with drug eluting stents). There was significant difference in restenosis rate between the bare mental stents andthedrugelutingstents(10/15vs3/25,P=0.001).Conclusion Endovascularstentingforthe treatment of the severe symptomatic vertebral artery ostial stenosis is a safe and efficient method. Although its restenosis rate is high,but it can improve the symptom of posterior circulation ischemia effectively.

Lateralizing language area and assessing hemispheric memory function by intracarotid injecting propofol / 中华神经科杂志

Objective In the context of worldwide shortage of amytal,explore the intracarotidpropofol test for lateralizing language area and assessing hemispheric memory function.Methods Fourteen patients with refractory partial epilepsy who were candidates for surgical intervention were included in the study.With guide under a digital subtraction angiography,propofol was injected in bilateral intracarotidsequentially.Muscle power deceasing to level 0 at the contralateral limb and eyes gazing to contralateral side were used as the mark of hemispheric anesthesia completely.The immediate language alterations were recorded.To evaluate the bilateral language and memory functions,the visual and auditory memory tasks were performed sequentially once patient could concentrate his attention ; and after limb muscle power recovering to normal level,patients were required to perform a free recall test.Any abnormal responses were recorded.Results Language dominant hemisphere was determined in 14 patients.Nine patients were confirmed as left language dominance,2 patients were right language dominance.The remained 3 patients were considered as bilateral language dominance.Meanwhile,the hemispheric memory function was able be evaluated in 13 patients.More than 67％ memory function was sustained in hemisphere contralateral to mesial temporal lesions.Transient responses including eye pain,facial muscle spasms,laughers and involuntary movements were observed.Conclusion Hemispheric language and memory functions can be assessed with direct intracarotidpropofol injection,and propofol could be an alternative drug to amobarbital used in the Wada test.

Ultrasound thrombolysis in patients with ischemic stroke / 国际脑血管病杂志

Intravenous thrombolysis is the only treatment that has the evidence of evidence-based medicine in acute ischemic stroke. However, the narrow time window has limited the treatment opportunities of many patients. Transcranial ultrasound thrombolysis is a very promising thrombolysis-assisted method, and transcranial ultrasound plus microbubble-assisted thrombolysis is the research hotspot in recent years. At present, more suitable ultrasonic instruments for thrombolysis and a number of ways of ultrasound-assisted thrombolysis are being developed.

The Application of Transcranial Doppler in Stroke Thrombolytic Therapy / 国际脑血管病杂志

Transcranial Doppler can be used for diagnosing,monitoring,identifying the site of arterial occlusion,selecting appropriate cases for thrombolysis,and monitoring arterial recanalization during intravenous thrombolysis,and intra-arterial and intravenous thrombolysis with recombinant tissue plasminogen activator,The continuous monitoring of low frequency transcranial ultrasound has the effect of assisted thrombolysis;however,there are still controversies on the frequencies used in clinical practice.Transcranial Doppler assisted with microbubble contrast agent may further enhance the effect of thrombolysis.