Thermal and Magnetic Dual-Responsive Catheter-Assisted Shape Memory Microrobots for Multistage Vascular Embolization.

Catheters navigating through complex vessels, such as sharp turns or multiple U-turns, remain challenging for vascular embolization. Here, we propose a novel multistage vascular embolization strategy for hard-to-reach vessels that releases untethered swimming shape-memory magnetic microrobots (SMMs) from the prior catheter to the vessel bifurcation. SMMs, made of organo-gel with magnetic particles, ensure biocompatibility, radiopacity, thrombosis, and fast thermal and magnetic responses. An SMM is initially a linear shape with a 0.5-mm diameter at 20 °C inserted in a catheter. It transforms into a predetermined helix within 2 s at 38 °C blood temperature after being pushed out of the catheter into the blood. SMMs enable agile swimming in confined and tortuous vessels and can swim upstream using helical propulsion with rotating magnetic fields. Moreover, we validated this multistage vascular embolization in living rabbits, completing 100-cm travel and renal artery embolization in 2 min. After 4 weeks, the SMMs maintained the embolic position, and the kidney volume decreased by 36%.

tPA-anchored nanorobots for in vivo arterial recanalization at submillimeter-scale segments.

Micro/nanorobots provide a promising approach for intravascular therapy with high precision. However, blood vessel is a highly complex system, and performing interventional therapy in those submillimeter segments remains challenging. While micro/nanorobots can enter submillimeter segments, they may still comprise nonbiodegradable parts, posing a considerable challenge for post-use removal. Here, we developed a retrievable magnetic colloidal microswarm, composed of tPA-anchored Fe3O4@mSiO2 nanorobots (tPA-nbots), to archive tPA-mediated thrombolysis under balloon catheter-assisted magnetic actuation with x-ray fluoroscopy imaging system (CMAFIS). By deploying tPA-nbot transcatheter to the vicinity of the thrombus, the tPA-nbot microswarms were magnetically actuated to the blood clot at the submillimeter vessels with high precision. After thrombolysis, the tPA-nbots can be retrieved via the CMAFIS, as demonstrated in ex vivo organ of human placenta and in vivo carotid artery of rabbit. The proposed colloidal microswarm provides a promising robotic tool with high spatial precision for enhanced thrombolysis with low side effects.

Preshaped 4D Photocurable Ultratough Organogel Microcoils for Personalized Endovascular Embolization.

Endovascular embolization using microcoils can be an effective technique to treat artery aneurysms. However, microcoils with fixed designs are difficult to adapt to all aneurysm types. In this paper, a photocurable ultratough shape memory organogel with a curing time of only 2 s and megapascal-level mechanical properties is proposed. Then, it is used to manufacture the personalized 4D microcoil with a wire diameter of only 0.3 mm. The improved mechanical modulus (511.63 MPa) can reduce the possibility of microcoils' fracture during embolization. Besides, the fast body-temperature-triggering shape memory ability makes the 4D microcoil applicable in vivo. These 4D microcoils are finally delivered into the rabbit, and successfully blocked the blood flow inside different aneurysms, with neoendothelial cells and collagen fibers growing on the microcoil surface snugly, indicating full aneurysm recovery. This 4D organogel microcoil can potentially be used in personalized clinical translation on human beings.

Recent progress in nanomedicines for imaging and therapy of brain tumors.

Nowadays, a malignant brain tumor is one of the most life-threatening diseases with poor prognosis, high risk of recurrence, and low survival rate for patients because of the existence of the blood-brain barrier (BBB) and the lack of efficient diagnostic and therapeutic paradigms. So far, many researchers have devoted their efforts to innovating advanced drugs to efficiently cross the BBB and selectively target brain tumors for optimal imaging and therapy outcomes. Herein, we update the most recent developments in nanomedicines for the diagnosis and treatment of brain tumors in preclinical mouse models. The special focus is on burgeoning drug delivery carriers to improve the specificity of visualization and to enhance the efficacy of brain tumor treatment. Also, we highlight the challenges and perspectives for the future development of brain tumor theranostics. This review is expected to receive wide attention from researchers, professors, and students in various fields to participate in future advancements in preclinical research and clinical translation of brain tumor nanomedicines.

Microrobots for Targeted Delivery and Therapy in Digestive System.

Untethered miniature robots enable targeted delivery and therapy deep inside the gastrointestinal tract in a minimally invasive manner. By combining actuation systems and imaging tools, significant progress has been made toward the development of functional microrobots. These robots can be actuated by external fields and fuels while featuring real-time tracking feedback toward certain regions and can perform the therapeutic process by rational exertion of the local environment of the gastrointestinal tract (e.g., pH, enzyme). Compared with conventional surgical tools, such as endoscopic devices and catheters, miniature robots feature minimally invasive diagnosis and treatment, multifunctionality, high safety and adaptivity, embodied intelligence, and easy access to tortuous and narrow lumens. In addition, the active motion of microrobots enhances local penetration and retention of drugs in tissues compared to common passive oral drug delivery. Based on the dissimilar microenvironments in the various sections of the gastrointestinal tract, this review introduces the advances of miniature robots for minimally invasive targeted delivery and therapy of diseases along the gastrointestinal tract. The imaging modalities for the tracking and their application scenarios are also discussed. We finally evaluate the challenges and barriers that retard their applications and hint on future research directions in this field.

Comparison of Electric Vehicle Lithium-Ion Battery Recycling Allocation Methods.

Power lithium-ion batteries (LIBs) are an important component of carbon neutrality in the transportation sector. The rapid growth of the LIB recycling industry is driven by various factors, such as resource scarcity. As a process interacting upstream and downstream, LIB recycling must consider the impact of the application of modeling approaches on the allocation of environmental benefits and burdens, especially at a time when carbon emissions are highly correlated with profit. In this study, seven allocation methods were chosen and applied to the production and multiple recycling process of typical LIB on the same data basis. The application of different allocation methods produced very disparate allocation results, and the conclusions of previous studies comparing the environmental performance of battery types need to be revisited. The life-cycle assessment (LCA) results should be interpreted with caution due to the impact of the allocation methods. Furthermore, a multi-indicator qualitative analysis based on product and process characteristics compares the applicability of the allocation methods to different aspects of LIB recycling. Relevant product standards for batteries should consider the characteristics of different methods and recommend a specific allocation method for the LCA community to employ in time to ensure that relevant studies are representative and comparable.

Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.

Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.

Localization diagnosis of adrenocorticotrophic hormone-dependent Cushing's syndrome: two case reports and literature review.

BACKGROUND: The common causes of adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS) include Cushing's disease (CD) and ectopic ACTH syndrome (EAS). The differential diagnosis and lesion location of CD and EAS often bring great difficulties to clinical diagnosis and treatment. This article reports the localization diagnosis, treatment, and follow-up results of two patients with ACTH-dependent CS with different causes and reviews the literature. CASE DESCRIPTION: Case 1: a 29-year-old female patient attended the clinic because of irregular menstruation, weight gain, and violaceous striae. The low dose dexamethasone suppression test (LDDST) was not suppressed, and the high dose dexamethasone suppression test (HDDST) suggested the results of serum cortisol and 24-h urine free cortisol were contradictory. Magnetic resonance imaging (MRI) indicated pituitary microadenoma, and bilateral inferior petrosal sinus sampling (BIPSS) indicated ACTH was centrally secreted. CD was diagnosed. The patient underwent transsphenoidal surgery, and the symptoms of CS were improved after the operation. A natural pregnancy occurred more than half a year after the surgery, and a healthy baby boy was delivered 9 months later. Case 2: a 29-year-old female patient complained of facial redness and elevated blood pressure. Examination showed refractory hypokalemia and abnormally elevated serum cortisol and ACTH. Androgens also increased. Neither LDDST nor HDDST was inhibited. Chest-to-pelvis computed tomography (CT) scan revealed a soft tissue mass in the anterior mediastinum, considered as a possible thymoma. EAS and thymoma were diagnosed. An anterior mediastinal mass resection was performed, and pathological results suggested thymic carcinoid weakly positive for ACTH. After the operation, hypertension and hypokalemia were relieved, and cortisol, ACTH and androgens returned to normal levels. CONCLUSIONS: The differentiation between CD and EAS should be comprehensively evaluated in combination with the medical history, function tests, pituitary MRI, and other tests. If the function test results are discordant or pituitary MRI shows the lesion diameter is less than 6 mm, BIPSS should be further performed to confirm the diagnosis. The lesions of EAS are complex and diverse, and it is necessary to pay attention to imaging examinations of the neck-to-pelvis to locate lesion and provide direction for subsequent treatment.

Phase separation drives the self-assembly of mitochondrial nucleoids for transcriptional modulation.

Mitochondria, the only semiautonomous organelles in mammalian cells, possess a circular, double-stranded genome termed mitochondrial DNA (mtDNA). While nuclear genomic DNA compaction, chromatin compartmentalization and transcription are known to be regulated by phase separation, how the mitochondrial nucleoid, a highly compacted spherical suborganelle, is assembled and functions is unknown. Here we assembled mitochondrial nucleoids in vitro and show that mitochondrial transcription factor A (TFAM) undergoes phase separation with mtDNA to drive nucleoid self-assembly. Moreover, nucleoid droplet formation promotes recruitment of the transcription machinery via a special, co-phase separation that concentrates transcription initiation, elongation and termination factors, and retains substrates to facilitate mtDNA transcription. We propose a model of mitochondrial nucleoid self-assembly driven by phase separation, and a pattern of co-phase separation involved in mitochondrial transcriptional regulation, which orchestrates the roles of TFAM in both mitochondrial nucleoid organization and transcription.

Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis.

OBJECTIVE: The aim of the present work was to investigate the response and safety of whole-brain radiotherapy (WBRT) plus temozolomide (TMZ) for patients with brain metastases of non-small-cell lung cancer (NSCLC). METHODS: The electronic databases of Pubmed, EMbase, Cochrane, Wangfang, china national knowledge infrastructure (CNKI), and Google scholar were systematically searched to identify the prospective randomized trials relevant to WBRT plus TMZ for patients with brain metastases of NSCLC. The data associated with treatment response and toxicity were extracted from original included studies. The relative risk (RR) for treatment response and toxicity between WBRT+TMZ and WBRT alone was pooled by fixed or random effect model. Publication bias was investigated by Begg's funnel plot and Egger's line regression test. RESULTS: Twenty-five clinical trials fulfilled the inclusion criteria and were included in the meta-analysis. The pooled results showed WBRT+TMZ can significant improve the objective response rate (ORR) compared with WBRT alone (RR = 1.43, 95% confidence interval [CI] 1.32-1.55, p < 0.05) under a fixed effect model. WBRT+TMZ significantly increased the III-IV hematological toxicity compared to WBRT alone (RR = 1.66, 95% CI 1.12-2.54, p < 0.05) in the fixed effect model. Grade III-IV gastrointestinal toxicity was increased in WBRT+TMZ compared to WBRT alone (RR = 1.72, 95% CI 1.29-2.30, p < 0.05). Begg's funnel plot and Egger's line regression test indicated publication bias. CONCLUSION: Based on the present work, WBRT+TMZ can improve the ORR for brain metastases of NSCLC, but the risk of treatment-associated grade III/IV hematological toxicity and gastrointestinal toxicity were also increased compared to WBRT alone.

METTL3 participates in glioma development by regulating the methylation level of COL4A1.

PURPOSE: The role of RNA methylation in human cancers has emerged. Its biological function in glioma development is explored in the present study. METHODS: Differential levels and prognostic potentials of COL4A1 and METTL3 in glioma were analyzed by bioinformatic method. The regulatory effect of METTL3 on COL4A1 was assessed through qRT-PCR, MeRIP and dual-luciferase reporter assay. Their biological functions in influencing proliferative and metastatic capacities of glioma cells were examined by EdU, colony formation and Transwell assay, respectively. RESULTS: COL4A1 was upregulated in glioma tissues, and METTL3 was downregulated. Knockdown of METTL3 in U87 and U251 cells could reduce the methylation level of COL4A1 and upregulate its expression level. Intervention of COL4A1 suppressed proliferative and metastatic capacities of glioma cells, while intervention of METTL3 yielded the opposite results. CONCLUSION: METTL3 reduces the methylation level of COL4A1 and upregulates its expression level, which further stimulates the malignant development of glioma. METTL3/COL4A1 can be potential therapeutic targets of glioma.

Modulation of proteoglycan receptor regulates RhoA/CRMP2 pathways and promotes axonal myelination.

The function of the myelinating system is important because a defective myelin sheath results in various nervous disorders, including multiple sclerosis and peripheral neuropathies. The dorsal root entry zone (DREZ) is a transitional area between the central nervous system (CNS) and the peripheral nervous system (PNS) that is generated by two types of cells-oligodendrocytes and Schwann cells (SCs). It is well known that after injury the extracellular matrix, including the CSPG, impairs axonal myelination by activating protein tyrosine phosphatase-σ (PTPσ) in both cells. The Intracellular Sigma Peptide (ISP) is memetic of the PTPσ wedge region. It competitively binds to PTPσ and regulates the downstream signaling of RhoA. In the present study, we aimed to investigate whether the ISP increased myelination in vivo and in vitro. The in vitro assay was meant to further verify the in vivo mechanisms. We observed that ISP administration could increase axonal myelination both in vivo and in vitro. Furthermore, we provide evidence that, in oligodendrocytes and Schwann cells, the myelination-induced effects of ISP application entail an inverse expression of the RhoA/CRMP2 signaling pathway. Overall, our results indicate that the ISP modulation of PTPσ enhances axonal myelination via the RhoA/CRMP2 signaling pathways.

The preparation of the ordered pores colloidal crystal scaffold and its role in promoting growth of lung cells.

Lung is one of important organs and lung diseases seriously affect the health of human beings. In this study, chitosan and gelatin as natural biological macromolecules raw material for the synthesis of ordered colloidal crystal scaffolds (CCS), Fe3O4 magnetic nanoparticles (MNPs) were used as pore-making for the first time. The pore-making agent were added into the hydrogels to synthesis the ordered (magnetic field) and disordered (no magnetic field) CCS. Collagen and basic fibroblast growth factor (bFGF) modified on the surface of CCS. Then mouse lung epithelial cells (TC-1) and normal human bronchial epithelial cells (Beas-2B) were cultured on the scaffold, obviously induced cell proliferation. Various physical and chemical characteristics indicate that the preparation of scaffolds and modified growth factors can greatly promote the proliferation of these two cells. In addition, the scafolld was implanted into the SD rat in vivo, and routine blood tests showed that the stent had a small inflammatory response to the rat. This may be one of the effective strategies for the future treatment of lung injury repair.

Dural Arteriovenous Fistulas at the Petrous Apex with Pial Arterial Supplies.

OBJECTIVE: Dural arteriovenous fistula (DAVF) at the petrous apex with pial arterial supplies possesses complicated angioarchitecture, associates with aggressive neurologic behaviors, and associates with high risk of complications. This study aimed to summarize our experience with this type of DAVF in the last 15 years. METHODS: This retrospective study reviewed 26 consecutive patients diagnosed with DAVFs of the petrous apex with pial arterial supplies from February 2002 to June 2017. Clinical information was extracted from medical records, radiographic data, intraoperative images, and complications and follow-up records. RESULTS: The 26 patients included 24 men and 2 women, with a mean age of 46.54 ± 12.49 years (range, 28-73 years). Manifestations included nonhemorrhagic neurologic defects (19/26, 73.1%), subarachnoid hemorrhage (SAH) (5/26, 19.2%), and no symptoms (2/26, 7.7%). Supratentorial draining direction was detected in 89.47% of the lesions, and 80% of the patients with venous ectasia had SAH. Complete occlusion was achieved in 21 patients (80.77%) through transarterial embolization and 5 patients (19.2%) through preoperative embolization combined with microsurgery. Complications included transient cranial nerve palsy in 1 patient (3.8%) and rebleeding in 2 patients (7.7%). The Barthel Index scores ranged from 10 to 100 (average, 66.73) and improved significantly (average, 96.62) in the follow-up period (10-175 months; median, 85.6 months). CONCLUSIONS: Supratentorial draining direction may be a risk factor for venous ectasia and SAH in petrous apex DAVFs with pial arterial supplies. The feeding pial arteries appeared to be at risk of embolization-related hemorrhagic complication and are therefore suggested to be embolized first.

Dural Arteriovenous Fistulas at the Petrous Apex.

OBJECTIVE: Dural arteriovenous fistulas (DAVFs) at the petrous apex are rare but may cause subarachnoid hemorrhage (SAH) or severe brainstem edema. This study aimed to summarize their clinical features and discuss the classification. METHODS: During a 15-year period, 64 consecutive patients with DAVF at the petrous apex were reviewed. According to their angioarchitecture, these cases were classified as follows: type I, no venous ectasia (48.4%); type II, venous ectasia but with normal vein proximal to the fistula (29.7%); and type III, venous ectasia at the site of the fistula (21.9%). RESULTS: There were 53 men and 11 women included. Presented symptoms were SAH in 8 patients (12.5%), nonhemorrhagic neurologic defects (NHNDs) in 53 patients (82.8%), and no symptoms in 3 patients (4.7%). There were 49 patients who received transarterial embolization, 8 patients who received microsurgery, and 7 patients who received embolization and microsurgery. Complications occurred in 9 patients (14.1%), including transient cranial nerve palsy (4.7%), rebleeding (6.3%), and respiratory failure (3.1%). Of the type I patients, 96.77% presented with NHNDs and 77.42% presented with infratentorial drainage. However, SAH occurred more often in type II (21.05%)/type III cases (28.57%), and most patients carried a supratentorial drainage (63.16% and 85.71%, respectively). In different types of DAVFs, the necessity for embolization combined with microsurgery (6.45% in type I, 10.53% in type II, 21.43% in type III) and the occurrence of rebleeding complications (0% in type I, 10.53% in type II, and 14.29% in type III) were varied. CONCLUSIONS: Petrous apex DAVFs carried a high risk of embolization-related complications. Based on the vascular architecture, this classification may reflect their clinical features and provide some advice on the treatment of DAVFs at the petrous apex.

Hybrid Operation of a Ruptured Aneurysm Associated with a Developmental Venous Anomaly.

BACKGROUND: As a normal variation of the cerebral venous angioarchitecture, developmental venous anomalies (DVAs) represent a rare cause of intraparenchymal hemorrhage. Different from mixed vascular lesions, such as capillary malformations, arteriovenous malformations, arteriovenous fistulas, and thrombosis, here we describe the first case of a ruptured hemodynamic aneurysm associated with a DVA and introduce the first use of hybrid operation for the treatment of a hemorrhagic DVA. METHODS: A 14-year-old girl suffered from sudden onset of headache, aphasia, and left hemiplegia. On the way of her transfer to our center, she suddenly fell into a coma. Computed tomography scan demonstrated an enlarged intraparenchymal hemorrhage in the left temporal lobe. Angiography revealed a large frontal DVA with an associated hemodynamic aneurysm. Superselective angiography of left middle cerebral artery confirmed that the aneurysm was located on the turning site of arteriovenous transition. RESULTS: Considering the large hematoma and the possible occlusion of surrounding collecting veins, we attempted transarterial embolization but were unsuccessful. Hematoma evacuation and aneurysm isolation were performed in a hybrid operation room. Intraoperative angiography was used to confirm the location of the aneurysm and to recheck the result. The patient woke up 1 day later and the symptoms were relieved entirely 1 year later. CONCLUSIONS: Associated aneurysm may be a cause of intraparenchymal hemorrhage in DVAs and routine imaging monitoring is needed. Hybrid operation is a possible treatment for such complicated mixed lesions in DVA, which proved to be safe and effective in this patient.

Combined Phycocyanin and Hematoporphyrin Monomethyl Ether for Breast Cancer Treatment via Photosensitizers Modified Fe3O4 Nanoparticles Inhibiting the Proliferation and Migration of MCF-7 Cells.

Photodynamic therapy (PDT), combining the laser and photosensitizers to kill tumor cells, has the potential to address many current medical requirements. In this study, magnetic Fe3O4 nanoparticles were first employed as cores and modified with oleic acid (OA) and 3-triethoxysilyl-1-propanamine. Then, the photosensitizers phycocyanin (PC) and hematoporphyrin monomethyl ether (HMME), which might be able to stimulate the cell release of reactive oxygen species after the irradiation of a near-infrared (NIR) laser, were grafted on the surface of such nanoparticles. Our results revealed the high-efficiency inhibition of breast cancer MCF-7 cells growing upon near-infrared irradiation both in vitro and in vivo. Furthermore, it was the synergy between the natural photosensitizers PC and the synthetic photosensitizers HMME that deeply influenced such inhibition compared to the groups that used either of these medicines alone. To utilize the combination of different photosensitive agents, our study thus provides a new strategy for breast cancer treatment.

Primary cerebral malignant melanoma: A case report with literature review.

Primary intracranial melanomas are uncommon and constitute approximately 1% of all melanoma cases and 0.07% of all brain tumors. In nature, these primary melanomas are very aggressive and can spread to other organs.We report an uncommon case of primary cerebral malignant melanoma-a challenging diagnosis guided by clinical presentations, radiological features, and surgical biopsy results, aiming to emphasize the importance of considering primary melanoma when making differential diagnoses of intracranial lesions.We present a rare case of a primary cerebral melanoma in the left temporal lobe. The mass appeared iso-hypodense on brain computed tomography (CT), short signal on T1-weighted magnetic resonance images (T1WI) and long signal on T2WI. It was not easy to make an accurate diagnosis before surgery. We showed the patient's disease course and reviewed related literatures, for readers' reference. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary.After surgery, the pathological examination confirmed the diagnosis of melanoma. The patient was discharged without any complications and went on to receive adjuvant radiochemotherapy.It is difficult to diagnose primary cerebral melanoma in the absence of any cutaneous melanosis. A high index of clinical suspicion along with good pathology reporting is the key in diagnosing these extremely rare tumors.