The mechanism and therapeutic strategies in Doxorubicin induced cardiotoxicity: Role of programmed cell death.

Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that the programmed cell death plays a significant role in doxorubicin induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy and ferroptosis. Furthermore, oxidative stress, inflammation and mitochondial dysfunction, are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathway of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including SIRT1/Nrf2, SIRT1/Klotho, SIRT1/SESN2, AMPK, AKT and PPAR. Heat Shock Proteins function as chaperones, which play important role in various stressful situations, especially in the heart. Thus, some of Heat Shock Proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above.

A highly integrated digital PCR system with on-chip heating for accurate DNA quantitative analysis.

Digital polymerase chain reaction (dPCR) is extensively used for highly sensitive disease diagnosis due to its single-molecule detection ability. However, current dPCR systems require intricate DNA sample distribution, rely on cumbersome external heaters, and exhibit sluggish thermal cycling, hampering efficiency and speed of the dPCR process. Herein, we presented the development of a microwell array based dPCR system featuring an integrated self-heating dPCR chip. By utilizing hydrodynamic and electrothermal simulations, the chip's structure is optimized, resulting in improved partitioning within microwells and uniform thermal distribution. Through strategic hydrophilic/hydrophobic modifications on the chip's surface, we effectively secured the compartmentalization of sample within the microwells by employing an overlaying oil phase, which renders homogeneity and independence of samples in the microwells. To achieve precise, stable, uniform, and rapid self-heating of the chip, the ITO heating layer and the temperature control algorithm are deliberately designed. With a capacity of 22,500 microwells that can be easily expanded, the system successfully quantified EGFR plasmid solutions, exhibiting a dynamic linear range of 105 and a detection limit of 10 copies per reaction. To further validate its performance, we employed the dPCR platform for quantitative detection of BCR-ABL1 mutation gene fragments, where its performance was compared against the QuantStudio 3D, and the self-heating dPCR system demonstrated similar analytical accuracy to the commercial dPCR system. Notably, the individual chip is produced on a semiconductor manufacturing line, benefiting from mass production capabilities, so the chips are cost-effective and conducive to widespread adoption and accessibility.

Two way workable microchanneled hydrogel suture to diagnose, treat and monitor the infarcted heart.

During myocardial infarction, microcirculation disturbance in the ischemic area can cause necrosis and formation of fibrotic tissue, potentially leading to malignant arrhythmia and myocardial remodeling. Here, we report a microchanneled hydrogel suture for two-way signal communication, pumping drugs on demand, and cardiac repair. After myocardial infarction, our hydrogel suture monitors abnormal electrocardiogram through the mobile device and triggers nitric oxide on demand via the hydrogel sutures' microchannels, thereby inhibiting inflammation, promoting microvascular remodeling, and improving the left ventricular ejection fraction in rats and minipigs by more than 60% and 50%, respectively. This work proposes a suture for bidirectional communication that acts as a cardio-patch to repair myocardial infarction, that remotely monitors the heart, and can deliver drugs on demand.

Intracranial mesenchymal tumor with multiple extracranial metastases: A case report and literature review.

This study presents a rare case of an older woman with an intracranial mesenchymal tumor in the right frontal and parietal lobes. Despite prompt surgical intervention, her condition rapidly deteriorated because of tumor dissemination, leading to her demise. We highlight the tumor's marked invasiveness and heterogeneity, coupled with a propensity for distant systemic metastasis, which negatively impacted the patient's prognosis. This particular clinical behavior had not been previously reported, making this a novel observation. Thus, through a comprehensive review of relevant literature, we aim to provide valuable insights for further understanding, diagnosing, and treating such tumors.

Engineered exosomes reprogram Gli1+ cells in vivo to prevent calcification of vascular grafts and autologous pathological vessels.

Calcification of autologous pathological vessels and tissue engineering blood vessels (TEBVs) is a thorny problem in clinic. However, there is no effective and noninvasive treatment that is available against the calcification of TEBVs and autologous pathological vessels. Gli1+ cells are progenitors of smooth muscle cells (SMCs) and can differentiate into osteoblast-like cells, leading to vascular calcification. Our results showed that the spatiotemporal distribution of Gli1+ cells in TEBVs was positively correlated with the degree of TEBV calcification. An anticalcification approach was designed consisting of exosomes derived from mesenchymal stem cells delivering lncRNA-ANCR to construct the engineered exosome-Ancr/E7-EXO. The results showed that Ancr/E7-EXO effectively targeted Gli1+ cells, promoting rapid SMC reconstruction and markedly inhibiting Gli1+ cell differentiation into osteoblast-like cells. Moreover, Ancr/E7-EXO significantly inhibited vascular calcification caused by chronic kidney disease. Therefore, Ancr/E7-EXO reprogrammed Gli1+ cells to prevent calcification of vascular graft and autologous pathological vessel, providing unique insights for an effective anticalcification.

Biomimetic Antithrombotic Tissue-Engineered Vascular Grafts for Converting Cholesterol and Free Radicals into Nitric Oxide.

Small-diameter tissue-engineered vascular grafts (sdTEVGs) are essential materials used in bypass or replacement surgery for cardiovascular diseases; however, their application efficacy is limited because of patency rates, especially under hyperlipidemia, which is also clinically observed in patients with cardiovascular diseases. In such cases, improving sdTEVG patency is challenging because cholesterol crystals easily cause thrombosis and impede endothelialization. Herein, the development of a biomimetic antithrombotic sdTEVG incorporating cholesterol oxidase and arginine into biomineralized collagen-gold hydrogels on a sdTEVG surface is described. Biomimetic antithrombotic sdTEVGs represent a multifunctional substrate for the green utilization of hazardous substances and can convert cholesterol into hydrogen peroxide, which can react with arginine to generate nitric oxide (NO). NO is a vasodilator that can simulate the antithrombotic action of endothelial cells under hyperlipidemic conditions. In vivo studies show that sdTEVGs can rapidly produce large amounts of NO via a cholesterol catalytic cascade to inhibit platelet aggregation, thereby improving the blood flow velocity and patency rates 60 days after sdTEVG transplantation. A practical and reliable strategy for transforming "harmful" substances into "beneficial" factors at early transplantation stages is presented, which can also promote vascular transplantation in patients with hyperlipidemia.

Engineering hiPSC-CM and hiPSC-EC laden 3D nanofibrous splenic hydrogel for improving cardiac function through revascularization and remuscularization in infarcted heart.

Cell therapy has been a promising strategy for cardiac repair after myocardial infarction (MI), but a poor ischemic environment and low cell delivery efficiency remain significant challenges. The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI, but it is unclear whether it could be used for human pluripotent stem cell (hiPSC) cultivation and provide a proper microenvironment for cell grafts against the ischemic environment. Herein, we developed a splenic extracellular matrix derived thermoresponsive hydrogel (SpGel). Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway, cell-substrate adhesion, cardiac muscle contraction and oxidation-reduction processes. In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells (iECs) and cardiomyocytes (iCMs) with enhanced function on SpGel. The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven. Furthermore, in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival, revascularization and remuscularization. In conclusion, we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts, which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.

Cosmetic and functional results of a newly reconstructed thumb by combining the phalanx of second toe and the great toenail flap transplantation.

BACKGROUND: Microsurgical toe-to-hand transfer is a gold standard when it comes to repairing a thumb defect. Great toenail flap, thumbnail valva flap, free great toe, and second toe transplantation are the common methods in thumb reconstruction. Second toe transplantation achieves good function, but poor esthetics. Great toe transplantation achieves better esthetics, but hindered walking, due to the foot's loss of the great toe and moreover suboptimal thumb function. It is difficult to maintain both functional and esthetic satisfaction in thumb reconstruction. METHODS: We experimented with three different methods of toe to hand transfer. From October 2009 to July 2019, 30 patients with traumatic thumb defects received one of 3 different kinds of thumb reconstruction in our clinic according to their level of amputation. Divided evenly into three groups of ten, group one received a great toe transplantation, group two received a second toe transplantation, and group three received a combined great toenail flap and second toe phalanx transplantation. Each of the patients' thumbs had different levels of amputation at the metatarsophalangeal joint (MPJ) or distal interphalangeal joint (DIPJ). RESULTS: One patient suffered from a partial flap necrosis and received a groin flap to cover the defect. No other thumbs had any complications. The functional and esthetic results of both the donor and the recipient sites were satisfactory. Results show that, for patients with traumatic thumb defects, the combined transfer of flap and second toe phalanx was the best option. CONCLUSIONS: Compared to the great toe or second toe transfer, combined free transfer of the great toenail flap and second toe phalanx achieved a substantially better functional and esthetic result in the thumb reconstruction.

Engineered-Macrophage Induced Endothelialization and Neutralization via Graphene Quantum Dot-Mediated MicroRNA Delivery to Construct Small-Diameter Tissue-Engineered Vascular Grafts.

Rapid endothelialization of tissue-engineered blood vessels (TEBVs) is an essential strategy to inhibit thrombosis, chronic inflammation and intimal hyperplasia after transplantation into the body. Monocytes will be recruited to the transplantation site and converted to macrophages after TEBV implantation. Macrophages play an important role in angiogenesis; however, whether engineered macrophages can be utilized to promote rapid endothelialization of TEBVs remains unclear. Thus, a cell bioreactor that can engineer macrophages via graphene quantum dot (GQD)-mediated microRNA (miR) delivery was built in the TEBV. Briefly, GQD-miR-150 linked by disulfide bonds was adopted to functionalize both the inner and outer TEBVs. The GQD-miR-150 conjugation as an intracellular gene delivery system was taken up by macrophages. Under the protection of GQDs, miR-150 was transfected into the cytosol, allowing continuous secretion of vascular endothelial growth factor (VEGF) via upregulation of HIF-1α protein expression, and promoted the migration of endothelial cells (ECs) in vitro. An in vivo study showed a rapid endothelialization of the inner TEBVs after transplantation for 7 days, especially a holonomic endothelial layer after 30 days. For the outer TEBVs, neovascularization (vasa vasorum) accompanied by nerve growth was observed around the adventitia on day 90. In conclusion, the designed cell bioreactor consisting of GQD-miR-engineered macrophages can effectively promote endothelialization and neuralization in vivo for TEBVs.

Surface-Engineered Monocyte Inhibits Atherosclerotic Plaque Destabilization via Graphene Quantum Dot-Mediated MicroRNA Delivery.

Rupture-prone atherosclerotic plaque is the cause of the high mortality and morbidity rates that accompany atherosclerosis-associated diseases. MicroRNAs can regulate the expression of a variety of atherosclerotic inflammation-related genes in macrophages. There are currently no definitive methods for delivering microRNAs into the interior of plaque. Monocytes typically possess a pathological feature that allows them to be recruited to atherosclerotic plaque resulting in rupture-prone; however, whether monocytes can be modified to be gene carriers remains unclear. In this study, a novel monocyte surface-engineered gene-delivery system based on graphene quantum dots (GQDs) is developed. Briefly, GQDs-microRNA223 linked by disulfide bonds are grafted onto the monocyte membrane via a carefully designed C18-peptide (C18P) containing a hydrophobic end to afford the designed monocyte-C18P-GQDs-miR223 architecture. The system can reach and enter the interior of the plaque and release the GQDs-miRNA via C18P digestion. The released GQDs-miRNA are taken up by the macrophages in atherosclerotic plaques, and the disulfide linkages between the GQDs and the miRNA are cleaved through γ-interferon-inducible lysosomal thiol reductase (GILT) in the lysosome. Under the protection of GQDs, miRNA cargos are transfected into the cytosol and subsequently undergo nuclear translocation, allowing a significantly reduced plaque burden by regulating inflammatory response in vivo.

The influence of cell morphology on microfluidic single cell analysis.

Microfluidics has been widely used in single cell analysis. Current protocols allow either spread or round cells to be analyzed. However, the contribution of cell morphology to single cell analysis has not been noted. In this study, four proteins (EGFR, PTEN, pAKT, and pS6) in the EGFR signaling pathway are measured simultaneously using microfluidic image cytometry (MIC) in glioblastoma cells U87. The results show that the MIC technology can reveal different subsets of cells corresponding to the four protein expression levels no matter whether they are round or spread at the time of the measurements. However, sharper distinction is obtained from round cells, which implies that cellular heterogeneity can be better resolved with round cells during in situ protein quantification by imaging cytometry. This study calls attention to the role of cell morphology in single cell analysis. Future studies should examine whether differences in data interpretation resulting from cell morphology could reveal altered biological meanings.

Construction of Antithrombotic Tissue-Engineered Blood Vessel via Reduced Graphene Oxide Based Dual-Enzyme Biomimetic Cascade.

Thrombosis is one of the biggest obstacles in the clinical application of small-diameter tissue-engineered blood vessels (TEBVs). The implantation of an unmodified TEBV will lead to platelet aggregation and further activation of the coagulation cascade, in which the high concentration of adenosine diphosphate (ADP) that is released by platelets plays an important role. Inspired by the phenomenon that endothelial cells continuously generate endogenous antiplatelet substances via enzymatic reactions, we designed a reduced graphene oxide (RGO) based dual-enzyme biomimetic cascade to successively convert ADP into adenosine monophosphate (AMP) and AMP into adenosine. We used RGO as a support and bound apyrase and 5'-nucleotidase (5'-NT) on the surface of RGO through covalent bonds, and then, we modified the surface of the collagen-coated decellularized vascular matrix with the RGO-enzyme complexes, in which RGO functions as a platform with a large open surface area and minimal diffusion barriers for substrates/products to integrate two catalytic systems for cascading reactions. The experimental results demonstrate that the two enzymes can synergistically catalyze procoagulant ADP into anticoagulant AMP and adenosine successively under physiological conditions, thus reducing the concentration of ADP. AMP and adenosine can weaken or even reverse the platelet aggregation induced by ADP, thereby inhibiting thrombosis. Adenosine can also accelerate the endothelialization of TEBVs by regulating cellular energy metabolism and optimizing the microenvironment, thus ensuring the antithrombotic function and patency of TEBVs even after the RGO-enzyme complex loses its activity.

A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly.

Myocardial infarction (MI) is a serious ischemic condition affecting many individuals around the world. Vascular endothelial growth factor (VEGF) is considered a promising factor for enhancing cardiac function by promoting angiogenesis. However, the lack of a suitable method of VEGF delivery to the MI area is a serious challenge. In this study, we screened a suitable delivery carrier with favorable biocompatibility that targeted the MI area using the strategy of an inherent structure derived from the body and that was based on characteristics of the MI. Mesenchymal stem cells (MSCs) are important infiltrating cells that are derived from blood and have an inherent tropism for the MI zone. We hypothesized that VEGF-encapsulated MSCs targeting MI tissue could improve cardiac function by angiogenesis based on the tropism of the MSCs to the MI area. We first developed VEGF-encapsulated MSCs using self-assembled gelatin and alginate polyelectrolytes to improve angiogenesis and cardiac function. In vitro, the results showed that VEGF-encapsulated MSCs had a sustained release of VEGF and tropism to SDF-1. In vivo, VEGF-encapsulated MSCs migrated to the MI area, enhanced cardiac function, perfused the infarcted area and promoted angiogenesis. These preclinical findings suggest that VEGF-loaded layer-by-layer self-assembled encapsulated MSCs may be a promising and minimally invasive therapy for treating MI. Furthermore, other drugs loaded to layer-by-layer self-assembled encapsulated MSCs may be promising therapies for treating other diseases.

[Clinical analysis of microsurgical treatment of giant intracranial arteriovenous malformations].

OBJECTIVE: To explore the clinical features and microsurgical treatment strategies of giant intracranial arteriovenous malformations (AVM). METHODS: A total of 15 cases of giant intracranial AVM treated with microsurgery were analyzed retrospectively. According to the Spetzler-Martin grade, there were 4 cases of grade Ⅳ, 11 cases of grade Ⅴ. Pre-operative endovascular embolizations were carried out in 3 AVMs. RESULTS: All the included patients were confirmed as giant intracranial AVM by magnetic resonance angiography (MRA), digital subtraction angiography (DSA), 3-dimensional CT angiography (3D-CTA) before surgery. All the resected tissues were sent for pathological examination, and the diagnoses were confirmed as AVM. The average operation time of the 15 patients was 10.3 ±6.9 hours. After 1-3 months, all the patients were rechecked by DSA, the large vascular malformations in 12 cases were completely resected, 3 cases had a small amount of residual further treated with gamma knife treatment. Magnetic resonance imaging (MRI) and MRA examination indicated that the residual AVM was occluded after 12 months. Patients were followed up at 6, 12 and 24 months after operation, and assessed by Glasgow outcome scale (GOS) score: 13 cases good, 1 cases mild disability, 1 cases severe disability; the good rate was 86.6%, with no dead case. CONCLUSION: Sufficiently preoperative preparation, appropriate operative methods and skills are necessary to treat giant intracranial arteriovenous malformation.

Detection of lung cancer with blood microRNA-21 expression levels in Chinese population.

The analysis of molecular markers in the biological field has been proposed as a useful tool for cancer diagnosis. MicroRNAs (miRNAs) may regulate diverse biological processes and play a significant role in tumorigenesis. The potential use of blood-based miRNAs as a biomarker of cancer and as a target for therapeutics is promising. The purpose of this study was to determine whether aberrant miRNA expression can be used as a molecular marker in peripheral blood for the diagnosis of lung cancer. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to analyze the expression levels of mature microRNA­21 (miR­21). Blood samples from 20 lung cancer patients and 10 healthy individuals were collected. The data were compared for the diagnosis of lung cancer. The results demonstrated that miR-21 was present in the peripheral blood in a markedly stable form and could be detected by real-time PCR sensitively and specifically. A significant difference was observed between the lung cancer cases and controls regarding miR-21 levels in peripheral blood (1947.26±930.56 pg/ml vs. 943.42±314.12 pg/ml, P=0.005). Furthermore, the over-expression of miR-21 showed a highly discriminative receiver operating characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with an area under the ROC curve (AUROC) of 0.912±0.045. The detection of miR­21 expression yielded 78.80% sensitivity and 100.00% specificity in the diagnosis of lung cancer. These findings indicate that in peripheral blood miR­21 may serve as a potential molecular marker for lung cancer and provide a new approach in the diagnosis of lung cancer.