Ischemia-reperfusion myocardial infarction induces remodeling of left cardiac-projecting stellate ganglia neurons.

Neurons in the stellate ganglion (SG) provide sympathetic innervation to the heart, brown adipose tissue (BAT), and other organs. Sympathetic innervation to the heart becomes hyperactive following myocardial infarction (MI). The impact of MI on the morphology of cardiac sympathetic neurons is not known, but we hypothesized that MI would stimulate increased cell and dendritic tree size in cardiac neurons. In this study, we examined the effects of ischemia-reperfusion MI on sympathetic neurons using dual retrograde tracing methods to allow detailed characterization of cardiac- and BAT-projecting neurons. Different fluorescently conjugated cholera toxin subunit B (CTb) tracers were injected into the pericardium and the interscapular BAT pads, respectively. Experimental animals received a 45-min occlusion of the left anterior descending coronary artery and controls received sham surgery. One week later, hearts were collected for assessment of MI infarct and SGs were collected for morphological or electrophysiological analysis. Cardiac-projecting SG neurons from MI mice had smaller cell bodies and shorter dendritic trees compared with sham animals, specifically on the left side ipsilateral to the MI. BAT-projecting neurons were not altered by MI, demonstrating the subpopulation specificity of the response. The normal size and distribution differences between BAT- and cardiac-projecting stellate ganglion neurons were not altered by MI. Patch-clamp recordings from cardiac-projecting left SG neurons revealed increased spontaneous excitatory postsynaptic currents despite the decrease in cell and dendritic tree size. Thus, increased dendritic tree size does not contribute to the enhanced sympathetic neural activity seen after MI.NEW & NOTEWORTHY Myocardial infarction (MI) causes structural and functional changes specifically in stellate ganglion neurons that project to the heart, but not in cells that project to brown adipose fat tissue.

Activatable endoplasmic reticulum-targeted NIR fluorescent probe with a large Stokes shift for detecting and imaging chymotrypsin.

In this work, the first endoplasmic reticulum-targeted near-infrared fluorescent probe, ISO-Chy, with a dicyanoisophorone derivative as a fluorophore is reported by introducing the recognition group of 4-bromobutyl for chymotrypsin detection. The probe can be easily synthesized and has shown satisfactory sensitivity and selectivity to chymotrypsin. Meanwhile, ISO-Chy has a large Stokes shift (135 nm) to minimize self-absorption and interference from autofluorescence and then generate significant fluorescence enhancement upon incubation with chymotrypsin. Additionally, ISO-Chy has an excellent ability to target the endoplasmic reticulum, along with preferable Pearson's correlation coefficients (Rr) of 0.9411 and 0.9522 in P815 cells and HepG2 cells, respectively. Moreover, ISO-Chy was successfully utilized to visualize endogenous chymotrypsin in P815 cells and HepG2 cells and was first used to detect chymotrypsin activity in HepG2 tumor-bearing mice. These findings indicate that ISO-Chy could be an effective tool for detecting endogenous chymotrypsin activity, supporting its use for investigating chymotrypsin function in pathologic processes.

Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. METHODS: We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. FINDINGS: We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3-/- mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. INTERPRETATION: Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. FUNDING: This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS "Light of West China" Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.).

Identification of Pulsatilla chinensis (Bge.) Regel and look-alike species by UHPLC-TOF-MS using multivariate statistical analysis.

Pulsatillae Radix, the root of Pulsatilla chinensis (Bge.) Regel, is recorded in the Pharmacopoeia of the People's Republic of China and has been widely used for its pharmacological activities, such as anti-inflammatory, antioxidant, antibacterial, antitumor, and cardiovascular benefits. However, there are several look-alike species that can be marketed as Pulsatillae Radix. To distinguish P. chinensis (Bge.) Regel from its look-alikes, viz. Pulsatilla cernua (Thunb.) Bercht et Opiz., Pulsatilla dahurica (Fisch.) Spreng., Anemone tomeutosa (Maxim.) Pei., and Rhaponticum uniflorum (L.) DC, we used ultra high performance liquid chromatography with time-of-flight mass spectrometry combined with principal component analysis to compare their chemical compositions. Four ions, a (RT 8.98 min, m/z 1381.6671), b (RT 10.64 min, m/z 1219.6143), c (RT 11.52 min, m/z 1217.5978), and d (RT 13.6 min, m/z 749.4463), from P. chinensis (Bge.) Regel were identified as potential chemical markers to distinguish it from look-alike species using an unsupervised statistical model combined with orthogonal partial least-squares discriminant analysis. The results of this study provide an effective method for identifying and distinguishing P. chinensis (Bge.) Regel from similar plants.

Pro-inflammatory microenvironment and systemic accumulation of CXCR3+ cell exacerbate lung pathology of old rhesus macaques infected with SARS-CoV-2.

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.

Northern pig-tailed macaques ( Macaca leonina) infected with SARS-CoV-2 show rapid viral clearance and persistent immune response.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques ( Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.

Remote Ischemic Conditioning in Cerebral Diseases and Neurointerventional Procedures: Recent Research Progress.

Cerebral ischemia and stroke are increasing in prevalence and are among the leading causes of morbidity and mortality in both developed and developing countries. Despite the progress in endovascular treatment, ischemia/reperfusion (IR) injury is an important contributor to post-surgical mortality and morbidity affecting a wide range of neurointerventional procedures. However, pharmacological recruitment of effective cerebral protective signaling has been largely disappointing to date. In remote ischemic conditioning (RIC), repetitive transient mechanical obstruction of vessels at a limb remote from the IR injury site protects vital organs from IR injury and confers infarction size reduction following prolonged arterial occlusion. Results of pharmacologic agents appear to be species specific, while RIC is based on the neuroprotective influences of phosphorylated protein kinase B, signaling proteins, nitric oxide, and transcriptional activators, the benefits of which have been confirmed in many species. Inducing RIC protection in patients undergoing cerebral vascular surgery or those who are at high risk of brain injury has been the subject of research and has been enacted in clinical settings. Its simplicity and non-invasive nature, as well as the flexibility of the timing of RIC stimulus, also makes it feasible to apply alongside neurointerventional procedures. Furthermore, despite nonuniform RIC protocols, emerging literature demonstrates improved clinical outcomes. The aims of this article are to summarize the potential mechanisms underlying different forms of conditioning, to explore the current translation of this paradigm from laboratory to neurovascular diseases, and to outline applications for patient care.

The toxicological mechanisms and detoxification of depleted uranium exposure.

Depleted uranium (DU) has been widely applied in industrial and military activities, and is often obtained from producing fuel for nuclear reactors. DU may be released into the environment, polluting air, soil, and water, and is considered to exert both radiological and chemical toxicity. In humans and animals, DU can induce multiple health effects, such as renal tubular necrosis and bone malignancies. This review summarizes the known information on DU's routes of entry, mechanisms of toxicity, and health effects. In addition, we survey the chelating agents used in ameliorating DU toxicity.

No inferiority of Tonbridge thrombectomy device for acute thrombus retrial compared with Solitaire device: an experimental evaluation with a canine distal external carotid-maxillary artery occlusion model.

INTRODUCTION: Mechanical thrombectomy (MT) has been widely accepted as a safe and effective treatment for acute ischemic stroke (AIS). Development of stent retriever devices has been intensively developed over the past two decades. In this study, we compared the effectiveness and safety of a new thrombectomy device with Solitaire FR for the treatment of AIS models. METHODS: Mechanical performance of stent retrievers was tested in vitro. Thrombin-induced thrombus was pre-injected into the right distal external carotid-maxillary artery in 18 dogs to create an acute thrombus occlusion model, and these animals were divided into a Tonbridge group (n=9, with Tonbridge stent Tonbridge Medical Technology) and a Solitaire group as control (n=9, with Solitaire stent, ev3 Neurovascular). Final flow restoration, side branches, recanalization time, distal vessel embolism, and device-related complications were recorded and compared. A post-procedure angiogram was obtained at 30 and 90 days after thrombectomy. Device manipulation-related damage to the arterial walls was evaluated histologically. RESULTS: In vitro test showed that the maximum friction within the microcatheter was 0.763 for the Tonbridge device and 0.784 n for the Solitaire (P>0.05). Slight increase in radial force was noticed for the Tonbridge (0.035 N/mm vs 0.031 N/mm of Solitaire, P>0.05). Eighteen and 16 retriever attempts were done in the Tonbridge (mean 2.0 attempts) and the Solitaire (mean 1.8 attempts) groups (P=0.74). The Tonbridge device led to good flow restoration in all nine (100%) models compared with eight (88.9%) in the Solitaire group (P=0.30). Side branches' influence (P=0.39), distal thromboembolism (P=0.60), and device-related complications (P=1.00) found no difference between the two groups. The rates of disruption of the internal elastic lamina (IEL) were 8.3% (2/24) and 4.2% (1/24) of the specimens, respectively (P=0.683). TICI 2b/3 flow of the right CCA were similar between the two groups at 1 (6/6 vs 6/6) and 3 months (6/6 vs 6/6) follow-up (P>0.05). CONCLUSION: Our preliminary study indicated this new device was technically feasible and effective to be used in thrombectomy for the treatment of acute thrombus occlusion in canine models.

Rapamycin enhances the anti-angiogenesis and anti-proliferation ability of YM155 in oral squamous cell carcinoma.

YM155, a small molecule inhibitor of survivin, has been studied in many tumors. It has been shown that YM155 inhibited oral squamous cell carcinoma through promoting apoptosis and autophagy and inhibiting proliferation. It was found that YM155 also inhibited the oral squamous cell carcinoma-mediated angiogenesis through the inactivation of the mammalian target of rapamycin pathway. Rapamycin, a mammalian target of rapamycin inhibitor, played an important role in the proliferation and angiogenesis of oral squamous cell carcinoma cell lines. In our study, cell proliferation assay, transwell assay, tube formation assay, and western blot assay were used to investigate the synergistic effect of rapamycin on YM155 in oral squamous cell carcinoma. Either in vitro or in vivo, rapamycin and YM155 exerted a synergistic effect on the inhibition of survivin and vascular endothelial growth factor through mammalian target of rapamycin pathway. Overall, our results revealed that low-dose rapamycin strongly promoted the sensitivity of oral squamous cell carcinoma cell lines to YM155.

Feasibility of Percutaneous Lumbar Discectomy Combined with Percutaneous Cementoplasty for Symptomatic Lumbar Disc Herniation with Modic Type I Endplate Changes.

BACKGROUND: Treatment of symptomatic lumbar disc herniation with Modic type I endplate changes is complex and challenging, requiring systemic and local therapies which include conservative therapy, epidural infiltrations, percutaneous therapeutic techniques, and surgical options. The clinical management of symptomatic lumbar disc herniation involving Modic type I endplate changes is uniquely challenging because it requires alleviating pain caused by both the herniated disc and the endplate osteochondritis. Through different approaches, percutaneous lumbar discectomy (PLD) and percutaneous cementoplasty (PCP) have been introduced into clinical practice as alternatives to traditional surgical and radiotherapy treatments of symptomatic lumbar disc herniation and other spine diseases. OBJECTIVE: To evaluate the feasibility of PLD and PCP for symptomatic lumbar disc herniation with Modic type I endplate changes. STUDY DESIGN: PLD and PCP in 7 patients with symptomatic lumbar disc herniation with Modic type I endplate changes and its clinical effects were retrospectively evaluated. SETTING: This study was conducted by an interventional therapy group at a medical center in a major Chinese city. METHODS: Seven consecutive patients (2 men, 5 women; median age, 74.14 ± 5.34 years; age range, 68 - 82 years) who underwent percutaneous lumbar discectomy and cementoplasty for the treatment of symptomatic lumbar disc herniation with Modic type I changes between May 2013 and August 2015 were retrospectively analyzed. The MacNab Criteria, visual analog scale (VAS), and Oswestry Disability Index (ODI) for pain were assessed before and one week, 6 months, and one year after the procedure. Furthermore, the procedure duration, hospital stay length, and complications were assessed. RESULTS: The VAS of the back and leg decreased from 6.14 ± 0.69 (range, 5 - 7) and 7.29 ± 0.76 (range, 6 - 8) preoperatively to 2.29 ± 1.38 (range, 1 - 5) and 2.71 ± 0.60 (range, 1 - 6) one week, 1.86 ± 0.69 (range, 1 - 3) and 2.00 ± 0.58 (range, 1 - 3) 6 months, and 1.71 ± 0.76 (range, 1 - 3) and 1.85 ± 0.69 (range, 1 - 3) one year postoperatively. The ODI dropped from 76.86 ± 7.45 (range, 70 - 82) preoperatively to 26.29 ± 19.47 (range, 16 - 70) one week, 19.14 ± 2.79 (range, 16 - 24) 6 months, and 18.57 ± 2.99 (range, 16 - 24) one year postoperatively. The mean procedure duration was 55.71 ± 6.07 minutes (range, 50 - 65 minutes). The average length of hospital stay was 7.57 ± 1.27 days (range, 6 - 10 days). No obvious complications were noted. LIMITATIONS: This was a retrospective study with a relatively small sample size. CONCLUSION: PLD plus PCP is a feasible technique for symptomatic lumbar disc herniation with Modic type I endplate changes.

Sidewall cerebral aneurysms: effect of an outflow angle-assisted approach on diagnosis.

BACKGROUND: The ability to diagnose sidewall cerebral aneurysms (SCAs) on an angle measurement basis may be useful in clinical practice. A study was undertaken to evaluate the effect of an outflow angle (OA)-assisted approach. METHODS: MR angiography (MRA) images of 438 patients with suspected SCAs and other cerebrovascular diseases were separately evaluated using the subjective approach and the OA approach. The approaches were then exchanged for confirmation of unclear cases. An OA of ≥90° was considered to represent SCA positivity. The accuracy, sensitivity, and specificity of the OA-assisted approach were determined using patient-based, aneurysm-based, and size-based evaluations. RESULTS: Digital subtraction angiography (DSA) detected 301 SCAs in 267 patients and no SCAs in 171. An OA of ≥90° was observed for 271 aneurysms in 244 patients (true positives); the OA approach misinterpreted OA as <90° for 29 aneurysms in 29 patients (false negatives) and missed one aneurysm. The subjective approach detected 309 SCAs in 273 patients. This approach misdiagnosed 10 patients (false positives) and missed two aneurysms in two patients (false negatives). The OA-assisted approach detected 300 SCAs in 267 patients and no SCAs in 171, overlooking one aneurysm. Patient-based evaluation yielded high accuracy, sensitivity, specificity, and positive and negative predictive values for the OA-assisted approach. CONCLUSIONS: The OA-assisted approach for SCA diagnosis effectively reduced the false-positive rate obtained with the subjective approach with high accuracy, sensitivity, and specificity, suggesting that MRA based on this approach can be a reliable alternative to DSA in SCA screening and diagnosis.

Aneurysm outflow angle at MRA as discriminant for accurate diagnosis and differentiation between small sidewall cerebral aneurysms and infundibula.

OBJECTIVE: To evaluate whether the aneurysm outflow angle (OA) at MR angiography (MRA) might serve as discriminant for accurate diagnosis of, and differentiation between, small sidewall cerebral aneurysms (SCAs) and infundibula. METHODS: Between June 2007 and July 2015, 426 consecutive patients with SCAs completed both an MRA and DSA examination. Of these, 156 patients with small SCAs and 52 patients with infundibula were included in this study. A patient with an OA ≥90° was defined as having a SCA, while those with OA <90° were defined as having an infundibulum. RESULTS: DSA identified 172 SCAs in 156 patients and 55 infundibula in 52 patients. The average OA on MRA was 102.96°±13.36° (range 60°-151°) in 172 SCAs of 156 patients. An OA of ≥90° was seen for 159 (92.4%) small SCAs in 147 patients, while an OA of <90° was observed for 13 SCAs. The average OA on MRA was 69.05°±14.26° (range 35-107°) in 55 infundibula of 52 patients. An OA of ≥90° was seen in one patient with one infundibulum; while an OA of <90° was observed for 54 infundibula (98.2%) in 51 patients. The average OA in SCAs (n=172) was greater than the average OA in infundibula (n=55; 102.96° vs 69.05°, p<0.001). CONCLUSIONS: The OA at MRA could serve as discriminant for accurate diagnosis of, and differentiation between, small SCAs and infundibula.

Percutaneous Vertebroplasty for Palliative Treatment of Painful Osteoblastic Spinal Metastases: A Single-Center Experience.

PURPOSE: To evaluate safety and efficacy of fluoroscopy-guided percutaneous vertebroplasty (PVP) for painful osteoblastic spinal metastases. MATERIALS AND METHODS: PVP was performed in 39 consecutive patients (median age, 60.1 y ± 9.5) with 51 osteoblastic metastatic spinal lesions; 14 patients had pathologic fractures. The patients were followed for 3-30 months (average, 14.5 mo ± 7.4). Visual analog scale (VAS), Oswestry Disability Index (ODI), and Karnofsky performance scale (KPS) were used to evaluate pain, quality of life, and performance status before the procedure and at 3 days and 1, 3, 6, 12, and 18 months after the procedure. RESULTS: Technical success was achieved in all patients. Minimal follow-up time was 3 months. Mean VAS scores declined significantly from 7.4 ± 1.1 before the procedure to 2.5 ± 0.9 by day 3 after the procedure and were 2.1 ± 1.1 at 1 month, 2.0 ± 1.1 at 3 months, 1.9 ± 1.1 at 6 months, 1.8 ± 0.9 at 12 months, and 1.7 ± 0.7 at 18 months after the procedure (P < .001). ODI and KPS scores also changed after the procedure, with significant differences between baseline scores and at each follow-up examination (P < .001). Extraosseous cement leakage occurred in 15 cases without causing any clinical complications. CONCLUSIONS: PVP is a safe and effective treatment for painful osteoblastic spinal metastases. It can relieve pain, reduce disability, and improve function.

Comparison of Percutaneous Cementoplasty with and Without Interventional Internal Fixation for Impending Malignant Pathological Fracture of the Proximal Femur.

PURPOSE: To compare the efficacy of percutaneous cementoplasty (PCP) with and without interventional internal fixation (IIF) on malignant impending pathological fracture of proximal femur. METHODS: A total of 40 patients with malignant impending pathological fracture of proximal femur were selected for PCP and IIF (n = 19, group A) or PCP alone (n = 21, group B) in this non-randomized prospective study. Bone puncture needles were inserted into the proximal femur, followed by sequential installation of the modified trocar inner needles through the puncture needle sheath. Then, 15-45 ml cement was injected into the femur lesion. RESULTS: The overall excellent and good pain relief rate during follow-ups were significantly higher in group A than that in group B (89 vs. 57 %, P = 0.034). The average change of VAS, ODI, KPS, and EFES in group A were significantly higher than those in group B at 1-, 3-, 6-month, 1-year (P < 0.05). Meanwhile, The stability of the treated femur was significantly higher in group A than that in group B (P < 0.05). CONCLUSION: PCP and IIF were not only a safe and effective procedure, but resulted in greater pain relief, bone consolidation, and also reduced the risk of fracture than the currently recommended approach of PCP done on malignant proximal femoral tumor.

Anti-tumor activities of active ingredients in Compound Kushen Injection.

Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study.

Cyr61/CCN1 overexpression induces epithelial-mesenchymal transition leading to laryngeal tumor invasion and metastasis and poor prognosis.

BACKGROUND: To examine the expression of cysteine-rich 61 (Cyr61/CCN1) protein in laryngeal squamous- cell carcinoma (LSCC) tissues, and its relationship with the tumor epithelial-mesenchymal transition (EMT), invasion, metastasis, and prognosis. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expressions of Cyr61, Vimentin (Vim), and E-cadherin (E-cad) in 88 cases of LSCC tissues and 30 cases of tumor-adjacent normal tissues. Vim and E-cad were used as mesenchymal and epithelial markers, respectively, to determine the relationship between Cyr61 expression and the EMT of LSCC cells. In addition, clinical and histopathological data were combined to analyze the relationship between the positive-expression rates of Cyr61, Vim and E-cad and LSCC invasion, metastasis and prognosis. RESULTS: In LSCC tissues, Vim expression rate was significantly higher than that of the tumor-adjacent tissues, whereas E-cad expression rate was significantly lower than that of the tumor-adjacent tissues. The Vim expression rate was significantly higher in stages T3 and T4 than in stages T1 and T2 LSCC tissues, whereas E-cad expression rate was significantly lower in stages T3 and T4 than in stages T1 and T2 LSCC tissues. Compared to the group without lymph node metastasis, the Vim expression rate was significantly higher and the E-cad expression rate was significantly lower in the group with lymph node metastasis. The expression rate of Cyr61 was significantly higher in LSCC tissues than in the tumor-adjacent normal tissues. In addition, the Cyr61 expression rate was higher in stages T3 and T4 than in stages T1 and T2 LSCC, and higher in the group with lymph node metastasis than in the group without lymph node metastasis. The Vim expression rate was significantly higher in the Cyr61 positive group than in the Cyr61 negative group, whereas the E-cad expression rate was significantly higher in the Cyr61 negative group than in the Cyr61 positive group. Survival analysis indicated that survival rates of Cyr61 positive, Vim positive and E-cad negative groups were significantly lower than that of Cyr61 negative, Vim negative and E-cad positive groups, respectively. CONCLUSIONS: Cyr61 expression is closely associated with LSCC invasion and lymph node metastasis. Overexpression of Cyr61 may induce EMT and therefore leads to LSCC invasion and metastasis and poor prognosis. Cyr61 may become a new maker for clinical prediction of LSCC invasion and metastasis and a new target for LSCC treatment.

Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells.

Breast cancer is one of the leading cancer-related causes of death worldwide. Treatment of triple-negative breast cancer (TNBC) is complex and challenging, especially when metastasis has developed. In this study, we applied infrared radiation as an alternative approach for the treatment of TNBC. We used middle infrared (MIR) with a wavelength range of 3-5 µm to irradiate breast cancer cells. MIR significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells. We performed iTRAQ-coupled LC-MS/MS analysis to investigate the MIR-triggered molecular mechanisms in breast cancer cells. A total of 1749 proteins were identified, quantified, and subjected to functional enrichment analysis. From the constructed functionally enriched network, we confirmed that MIR caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability. Our results reveal the coordinative effects of MIR-regulated physiological responses in concentrated networks, demonstrating the potential implementation of infrared radiation in breast cancer therapy.

Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a dismal prognosis. Despite intensive study on tumor biology, the underlying mechanisms of the unlimited proliferation and progressive local invasion are still poorly understood, and no effective treatment has been developed for GBM patients. AIMS: We determine the role of TRPM7 channels in the growth, migration, and infiltration of malignant glioma cells. METHODS: Using a combination of RT-PCR, Western blot, and patch-clamp techniques, we demonstrated the expression of functional TRPM7 channels of A172 cells, a human glioma cell line, as well as in human glioma tissues. Furthermore, we evaluated the role of TRPM7 in growth, migration, and infiltration of A172 cells with MTT and transwell migration and invasion assays. RESULTS: We showed the expression of functional TRPM7 channels in both A172 cells and human glioma tissues. Suppression of TRPM7 expression with TRPM7-siRNA dramatically reduced the proliferation, migration, and invasion of A172 cells. Pharmacological inhibition of TRPM7 channel with 2-aminoethoxydiphenyl borate (2-APB) showed a similar effect as TRPM7-siRNA. CONCLUSION: We demonstrate that human glioma cells express functional TRPM7 channel and that activation of this channel plays an important role in the proliferation, migration, and invasion of malignant glioma cells. TRPM7 channel may represent a novel and promising target for therapeutic intervention of malignant glioma.

Arterial wall degeneration plus hemodynamic insult cause arterial wall remodeling and nascent aneurysm formation at specific sites in dogs.

To determine whether arterial wall degeneration, in combination with hemodynamic insult, causes cerebral artery aneurysms in a dog model, we simulated the geometry and hemodynamics of a human artery by surgical reconstruction of both common carotid arteries in 12 dogs. The dogs were then randomly assigned to one of the following groups: hemodynamic insult + elastase insult group ( n = 6), hemodynamic insult group (n = 6), or elastase control group (n = 3), in which the straight common carotid arteries were subjected to elastase alone. Angiography and hemodynamic analysis were performed immediately and at 12 weeks after surgery; the animals were then killed for histologic evaluation. The 12 surgically reconstructed distal internal carotid arteries simulated the human artery well with respect to geometric and hemodynamic measurements, with the intended aneurysm sites exposed to higher wall shear stress and velocity, lower pressure, turbulent flow, and changes in wall shear stress gradient. Nascent aneurysms developed in 4 hemodynamic insult + elastase insult group dogs at 12 weeks; blood flow analysis demonstrated decreased wall shear stress, increased pressure, and wall shear stress gradient from the neck to the dome. Arterial wall remodeling or nascent aneurysm formation in the hemodynamic insult + elastase insult group versus the other groups was indicated by internal elastic lamina/elastic fiber disruption, muscular layer thinning, increased smooth muscle cell proliferation, macrophage infiltration, and high expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the media. These data suggest that nascent aneurysms were caused by the combination of arterial wall degeneration and hemodynamic perturbations in this distal internal carotid artery dog model.