Effect of mechanical thrombectomy with and without intravenous thrombolysis on the functional outcome of patients with different degrees of thrombus perviousness.

PURPOSE: This study aimed to investigate the long-term functional outcome of patients with different degrees of thrombus perviousness (TP) undergoing mechanical thrombectomy alone and those undergoing combined intravenous thrombolysis (IVT) plus mechanical thrombectomy. METHODS: We conducted a retrospective analysis of consecutive patients with acute ischemic stroke due to large vessel occlusion who underwent mechanical thrombectomy alone or bridging therapy between January 2016 and October 2020. TP was quantified by thrombus attenuation increase (TAI) on admission computed tomography angiography compared with non-contrast computed tomography. After dichotomization of TAI as higher or lower perviousness, Fisher exact tests were performed to estimate the associations of different therapies with favorable functional outcomes [Modified Ranking Scale score at 90 days (90-day mRS) of 0 to 2]. RESULTS: A total of 73 patients were included in our study. 35 (47.9%) thrombi were classified as higher-perviousness clots with TAI of ≥ 24 HU, and the other 38 thrombi were lower-perviousness clots. A favorable outcome with a 90-day mRS of 0 to 2 was observed in 32 patients. In patients with thrombi of lower perviousness, favorable outcome was more common in the bridging therapy group than in the thrombectomy-alone group (p = 0.013), whereas in patients with thrombi of higher perviousness, the long-term neurological outcome did not significantly differ between two therapy groups (p = 0.094). CONCLUSION: Patients with thrombi of lower perviousness were recommended to undergo intravenous alteplase followed by endovascular thrombectomy, and those with thrombi of higher perviousness could undergo thrombectomy alone.

Iron homeostasis imbalance and ferroptosis in brain diseases.

Brain iron homeostasis is maintained through the normal function of blood-brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients' outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron-dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

MRI characteristics of lumbosacral dural arteriovenous fistulas.

Background and purpose: Spinal dural arteriovenous fistulas located in the lumbosacral region are rare and present with nonspecific clinical signs. The purpose of this study was to find out the specific radiologic features of these fistulas. Methods: We retrospectively reviewed the clinical and radiological data of 38 patients diagnosed with lumbosacral spinal dural arteriovenous fistulas in our institution from September 2016 to September 2021. All patients underwent time-resolved contrast-enhanced three-dimensional MRA and DSA examinations, and were treated with either endovascular or neurosurgical strategies. Results: Most of the patients (89.5%) had motor or sensory disorders in both lower limbs as the first symptoms. On MRA, the dilated filum terminale vein or radicular vein was seen in 23/30 (76.7%) patients with lumbar spinal dural arteriovenous fistulas and 8/8 (100%) patients with sacral spinal dural arteriovenous fistulas. T2W intramedullary abnormally high signal intensity areas were found in all lumbosacral spinal dural arteriovenous fistula patients, with involvement of the conus present in 35/38 (92.1%) patients. The "missing piece sign" in the intramedullary enhancement area was seen in 29/38 (76.3%) patients. Conclusion: Dilatation of the filum terminale vein or radicular vein is powerful evidence for diagnosis of lumbosacral spinal dural arteriovenous fistulas, especially for sacral spinal dural arteriovenous fistulas. T2W intramedullary hyperintensity in the thoracic spinal cord and conus, and the missing-piece sign could be indicative of lumbosacral spinal dural arteriovenous fistula.

Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. Aerobic glycolysis is a hallmark of reprogrammed metabolic activity in cancer cells, which can be repressed by small-interfering RNA (siRNA). However, the lack of effective carriers to deliver vulnerable siRNA restricts the clinical potentials of glycolysis-based gene therapy for TNBC. Herein, we develop a tumor-targeted, biomimetic manganese dioxide (MnO2)-shrouded metal-organic framework (MOF) based nanomedicine to deliver siRNA against pyruvate kinase muscle isozyme M2 (siPKM2), wherein PKM2 is a rate-limiting enzyme in glycolysis, to inhibit the reprogrammed glycolysis of TNBC. This MOF-based genetic nanomedicine shows excellent monodispersity and stability and protects siPKM2 against degradation by nucleases. The nanomedicine not only substantially blocks the glycolytic pathway but also improves intracellular hypoxia in TNBC cells, with a resultant O2-enhanced anticancer effect. In the mice orthotopic TNBC model, the nanomedicine shows a remarkable therapeutic effect. Meanwhile, the Mn2+ ions released from acid microenvironment-responsive MnO2 enable in vivo monitoring of the therapeutic process with magnetic resonance imaging (MRI). Our study shows great promise with this MRI-visible MOF-based nanomedicine for treating TNBC by inhibition of glycolysis via the RNA interference.

Radiomics model based on preoperative gadoxetic acid-enhanced MRI for predicting liver failure.

BACKGROUND: Postoperative liver failure is the most severe complication in cirrhotic patients with hepatocellular carcinoma (HCC) after major hepatectomy. Current available clinical indexes predicting postoperative residual liver function are not sufficiently accurate. AIM: To determine a radiomics model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging for predicting liver failure in cirrhotic patients with HCC after major hepatectomy. METHODS: For this retrospective study, a radiomics-based model was developed based on preoperative hepatobiliary phase gadoxetic acid-enhanced magnetic resonance images in 101 patients with HCC between June 2012 and June 2018. Sixty-one radiomic features were extracted from hepatobiliary phase images and selected by the least absolute shrinkage and selection operator method to construct a radiomics signature. A clinical prediction model, and radiomics-based model incorporating significant clinical indexes and radiomics signature were built using multivariable logistic regression analysis. The integrated radiomics-based model was presented as a radiomics nomogram. The performances of clinical prediction model, radiomics signature, and radiomics-based model for predicting post-operative liver failure were determined using receiver operating characteristics curve, calibration curve, and decision curve analyses. RESULTS: Five radiomics features from hepatobiliary phase images were selected to construct the radiomics signature. The clinical prediction model, radiomics signature, and radiomics-based model incorporating indocyanine green clearance rate at 15 min and radiomics signature showed favorable performance for predicting postoperative liver failure (area under the curve: 0.809-0.894). The radiomics-based model achieved the highest performance for predicting liver failure (area under the curve: 0.894; 95%CI: 0.823-0.964). The integrated discrimination improvement analysis showed a significant improvement in the accuracy of liver failure prediction when radiomics signature was added to the clinical prediction model (integrated discrimination improvement = 0.117, P = 0.002). The calibration curve and an insignificant Hosmer-Lemeshow test statistic (P = 0.841) demonstrated good calibration of the radiomics-based model. The decision curve analysis showed that patients would benefit more from a radiomics-based prediction model than from a clinical prediction model and radiomics signature alone. CONCLUSION: A radiomics-based model of preoperative gadoxetic acid-enhanced MRI can be used to predict liver failure in cirrhotic patients with HCC after major hepatectomy.

Smartphone-assisted robust enzymes@MOFs-based paper biosensor for point-of-care detection.

Portable devices featured with fast analysis and affordable methodologies for clinical diagnostics have stimulated the rapid development of point-of-care (POC) technologies, potentially lowering the mortality rate. Herein, we demonstrated a portable, robust, and user-friendly intelligent metal-organic frameworks (MOFs) paper device, called smartphone-assisted biomimetic MOFs nanoreactor colorimetric paper (SBMCP), for on-demand POC detection of endogenous biomolecules. The concept of this paper platform was analogous to the intracellular cascades signal transduction, wherein the single/multiple enzymes components trapped within a ZIF-8 exoskeleton allowed the sensitive and selective recognition of target analyte via the accessible micropores network of ZIF-8, and then transferred the recognition event to a visual color signal based on the cascade reaction. Meanwhile, the ZIF-8 exoskeleton also endowed the enzymes with significantly elevated stability. As a result, this robust and portable SBMCP sensor enabled the on-site analysis of different important disease-related biomolecules through modulating the enzyme cascades, combining with a custom-designed smartphone application for signal readout. In the SBMCP assay, no sophisticated instruments or professional skill of the user was required, only 5 µL sample volume was needed, and the whole analysis process could be achieved within a portable MOFs paper and pervasive smartphone, endowing this new assay with the merits of low-cost, time-saving and easy-to-use. We demonstrated this SBMCP sensor was capable of real-time colorimetric detection of glucose and uric acid in diabetes and gout events. It is believed that this portable biosensor platform proposed herein potentially represents promising alternatives for POC diagnosis, especially applicable in developing world and resource-limited settings.

Peritumoral administration of IFNß upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model.

BACKGROUND: Immunotherapy with IFNß is a promising strategy for treating malignant glioma. However, systemic administration of IFNß is inadequate because of low intratumoral concentration and major adverse effects. This study aimed to determine whether mesenchymal stem cells (MSCs) can be used as cellular vehicles to locally deliver IFNß for glioma therapy by using in vivo MRI tracking. METHODS: A recombinant lentiviral vector encoding IFNß and ferritin heavy chain (FTH) reporter genes was constructed to transduce MSCs. The effectiveness and safety of transduction were assessed. After the IFNß and FTH overexpressed MSCs (IFNß-FTH-MSCs) were transplanted into intracranial orthotopic rat F98 gliomas via peritumoral, intracerebral, intratumoral or intra-arterial injection, MRI was performed to track IFNß-FTH-MSCs and to evaluate their therapeutic effect on glioma in vivo, as validated by histologic analysis, quantitative PCR and ELISA assays. RESULTS: MSCs were efficiently and safely transduced to upregulate their IFNß secretion and FTH expression by the constructed lentivirus. After peritumoral injection, IFNß-FTH-MSCs appeared as hypointense signals on MRI, which gradually diminished but remained visible until 11 days. Compared with other administration routes, only peritumoral injection of IFNß-FTH-MSCs showed a remarkable inhibition on the glioma growth. Nearly 30% of IFNß-FTH-MSCs survived up to 11 days after peritumoral injection, while most of IFNß-FTH-MSCs injected via other routes died within 11 days. IFNß-FTH-MSCs grafted peritumorally secreted IFNß persistently, leading to pronounced Batf3+ dendritic cells and CD8+ T lymphocyte infiltration within the glioma. CONCLUSIONS: MSCs can be used as cellular vehicles of IFNß to treat malignant glioma effectively via peritumoral injection.

Modulating the Biofunctionality of Metal-Organic-Framework-Encapsulated Enzymes through Controllable Embedding Patterns.

Embedding an enzyme within a MOF as exoskeleton (enzyme@MOF) offers new opportunities to improve the inherent fragile nature of the enzyme, but also to impart novel biofunctionality to the MOF. Despite the remarkable stability achieved for MOF-embedded enzymes, embedding patterns and conversion of the enzymatic biofunctionality after entrapment by a MOF have only received limited attention. Herein, we reveal how embedding patterns affect the bioactivity of an enzyme encapsulated in ZIF-8. The enzyme@MOF can maintain high activity when the encapsulation process is driven by rapid enzyme-triggered nucleation of ZIF-8. When the encapsulation is driven by slow coprecipitation and the enzymes are not involved in the nucleation of ZIF-8, enzyme@MOF tends to be inactive owing to unfolding and competing coordination caused by the ligand, 2-methyl imidazole. These two embedding patterns can easily be controlled by chemical modification of the amino acids of the enzymes, modulating their biofunctionality.

Exosomal PD-L1 functions as an immunosuppressant to promote wound healing.

Excessive and persistent inflammation after injury lead to chronic wounds, increased tissue damage or even aggressive carcinogenic transformation. Effective wound repair could be achieved by inhibiting overactive immune cells to the injured site. In this study, we obtained high concentration of PD-L1 in exosomes from either genetically engineered cells overexpressing PD-L1 or IFN-γ stimulated cells. We found that exosomal PD-L1 is specially bound to PD-1 on T cell surface, and suppressed T cell activation. Interestingly, exosomal PD-L1 promoted the migration of epidermal cells and dermal fibroblasts when pre-incubated with T cells. We further embedded exosomes into thermoresponsive PF-127 hydrogel, which was gelatinized at body temperature to release exosomes to the surroundings in a sustained manner. Of importance, in a mouse skin excisional wound model, exosomal PD-L1 significantly fastened wound contraction and reepithelialization when embedded in hydrogel during inflammation phase. Finally, exosomal PD-L1 inhibited cytokine production of CD8+ T cells and suppressed CD8+ T cell numbers in spleen and peripheral lymph nodes. Taken together, these data provide evidence on exosomal PD-L1 exerting immune inhibitory effects and promoting tissue repair.

Computed tomography and magnetic resonance imaging evaluation of pelvic lymph node metastasis in bladder cancer.

BACKGROUND: Accurate evaluation of lymph node metastasis in bladder cancer (BCa) is important for disease staging, treatment selection, and prognosis prediction. In this study, we aimed to evaluate the diagnostic accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) for metastatic lymph nodes in BCa and establish criteria of imaging diagnosis. METHODS: We retrospectively assessed the imaging characteristics of 191 BCa patients who underwent radical cystectomy. The data regarding size, shape, density, and diffusion of the lymph nodes on CT and/or MRI were obtained and analyzed using Kruskal-Wallis test and χ2 test. The optimal cutoff value for the size of metastatic node was determined using the receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 184 out of 3317 resected lymph nodes were diagnosed as metastatic lymph nodes. Among 82 imaging-detectable lymph nodes, 51 were confirmed to be positive for metastasis. The detection rate of metastatic nodes increased along with more advanced tumor stage (P < 0.001). Once the ratio of short- to long-axis diameter ≤ 0.4 or fatty hilum was observed in lymph nodes on imaging, it indicated non-metastases. Besides, lymph nodes with spiculate or obscure margin or necrosis indicated metastases. Furthermore, the short diameter of 6.8 mm was the optimal threshold to diagnose metastatic lymph node, with the area under ROC curve of 0.815. CONCLUSIONS: The probability of metastatic nodes significantly increased with more advanced T stages. Once lymph nodes are detected on imaging, the characteristic signs should be paid attention to. The short diameter > 6.8 mm may indicate metastatic lymph nodes in BCa.

A Review of Resveratrol as a Potent Chemoprotective and Synergistic Agent in Cancer Chemotherapy.

Background: Cancer has become a major disease endangering human health around the world. Conventional chemotherapy suffers from many side effects including pain, cardiotoxicity, hepatotoxicity, and renal toxicity. This review aims to describe a natural product of resveratrol as a chemoprotective and synergistic agent in the modulation of cancer chemotherapy. Methods: The publications were identified by comprehensive searching of SciFinder, PubMed, Web of Science, and our own reference library. Search terms included combinations of "resveratrol," "cancer," "natural products," "chemotherapy," and "side effects." Selection of material focused on resveratrol reducing the side effects on cancer chemotherapy. Results: Thirty one references were referred in this review to outline resveratrol as a potent chemoprotective and synergistic agent in cancer chemotherapy, including 22 papers for describing the chemoprotective effects, and 9 papers for illustrating the synergistic effects. Conclusion: This study provides a systematic summary of resveratrol serving as a potent chemoprotective and synergistic agent to reduce the associated-side effects and enhance the therapeutic outcomes in cancer chemotherapy. Further studies in terms of resveratrol on a large amount of preclinical tests and clinical trials are highly demanded.