Vancomycin-Loaded Sol-Gel System for In Situ Coating of Artificial Bone to Prevent Surgical Site Infections.

Surgical site infections (SSIs) related to implants have always been a major challenge for clinical doctors and patients. Clinically, doctors may directly apply antibiotics into the wound to prevent SSIs. However, this strategy is strongly associated with experience of doctors on the amount and the location of antibiotics. Herein, an in situ constructable sol-gel system is developed containing antibiotics during surgical process and validated the efficacy against SSIs in beagles. The system involves chitosan (CS), ß-glycerophosphate (ß-GP) and vancomycin (VAN), which can be adsorbed onto porous hydroxyapatite (HA) and form VAN-CS/ß-GP@HA hydrogel in a short time. The VAN concentration from VAN-CS/ß-GP@HA hydrogel is higher than minimum inhibitory concentration (MIC) against Staphylococcus aureus (S. aureus) at the 21st day in vitro. In an in vivo canine model for the prevention of SSIs in the femoral condyle, VAN-CS/ß-GP@HA exhibits excellent biocompatibility, antimicrobial properties, and promotion of bone healing. In all, the CS/ß-GP instant sol-gel system is able to in situ encapsulate antibiotics and adhere on artificial bone implants during the surgery, effectively preventing SSIs related to implants.

Esculentoside H reduces the PANoptosis and protects the blood-brain barrier after cerebral ischemia/reperfusion through the TLE1/PI3K/AKT signaling pathway.

AIMS: Matrix metalloproteinases 9 (MMP9) plays a role in the destruction of blood-brain barrier (BBB) and cell death after cerebral ischemic/reperfusion (I/R). Esculentoside H (EH) is a saponin found in Phytolacca esculenta. It can block JNK1/2 and NF-κB signal mediated expression of MMP9. In this study, we determined whether EH can protect against cerebral I/R injury by inhibiting MMP9 and elucidated the underlying mechanism. MAIN METHODS: Male SD rats were used to construct middle cerebral artery occlusion (MCAO) models. We determined the effect of EH on MMP9 inhibition, BBB destruction, neuronal death, PANoptosis, infarct volume, and the protective factor TLE1. Adeno-associated virus (AAV) infection was used to establish TLE1 gene overexpression and knockdown rats, which were used to determine the function. LY294002 was used to determine the role of PI3K/AKT signaling in TLE1 function. KEY FINDINGS: After EH treatment, MMP9 expression, BBB destruction, neuronal death, and infarct volume decreased. We found that TLE1 expression decreased obviously after cerebral I/R. TLE1-overexpressing rats revealed distinct protective effects to cerebral I/R injury. After treatment with LY294002, the protective effect was inhibited. The curative effect of EH also decreased when TLE1 was knocked down. SIGNIFICANCE: EH alleviates PANoptosis and protects BBB after cerebral I/R via the TLE1/PI3K/AKT signaling pathway. Our findings reveal a novel strategy and new target for treating cerebral I/R injury.

Evaluation of the correlation between trigeminal nerve atrophy and trigeminal neuralgia using multimodal image fusion: A single-center retrospective study.

BACKGROUND: 3D-Slicer is an open-source medical image processing and visualization software. In the surgical treatment of trigeminal neuralgia, it is commonly used to predict the responsible vessels. However, there are few reports on the use of 3D-Slicer software to quantitatively measure the bilateral trigeminal nerve volume in patients with primary trigeminal neuralgia (PTN) based on the three-dimensional images. Therefore, this study aims to explore the role of three-dimensional fused images processed by 3D-Slicer in the evaluation of trigeminal nerve atrophy, providing an objective basis for the diagnosis of PTN. METHODS: 57 PTN patients who underwent microvascular decompression (MVD) or percutaneous balloon compression (PBC) surgery in Hebei general hospital between January 2020 and April 2023 were included. Additionally, 30 patients with facial spasms(HFS) were included as a control group. All patients underwent 3D-TOF-MRA and 3D-FIESTA sequence examinations. Comparisons of bilateral trigeminal nerve volumes within and between groups were conducted by performing image fusion using 3D-slicer. RESULTS: The volume of the affected trigeminal nerve in the MVD group (33.96 mm³±12.61 mm³) and PBC group (23.05 mm³±7.71 mm³) was smaller than that of the unaffected trigeminal nerve in the MVD group (39.61 mm³±12.83 mm³) and PBC group (26.14 mm³±6.42 mm³), as well as the average volume of the trigeminal nerve in the control group (40.27 mm³±10.25 mm³) (P<0.05). The differences in bilateral trigeminal ganglion volume (∆V) was significant between the MVD group (∆V=23.59 %±14.32 %) and the control group (∆V=14.64 %±10.00 %) (P<0.05). There was no statistical difference in the trigeminal nerve volume difference between the MVD group (∆V=23.59 %±14.32 %) and the PBC group (∆V=26.52 %±15.00 %) (P>0.05). CONCLUSION: Trigeminal nerve atrophy is correlated with primary trigeminal neuralgia. 3D-slicer software can quantitatively measure trigeminal nerve volume and assist in the diagnosis of primary trigeminal neuralgia based on the difference in bilateral trigeminal nerve volumes. However, trigeminal nerve atrophy is not associated with postoperative pain recurrence in patients.

Tumor Microenvironment-Responsive Nanocapsule Delivery CRISPR/Cas9 to Reprogram the Immunosuppressive Microenvironment in Hepatoma Carcinoma.

Cancer immunotherapy has demonstrated significant efficacy in various tumors, but its effectiveness in treating Hepatocellular Carcinoma (HCC) remains limited. Therefore, there is an urgent need to identify a new immunotherapy target and develop corresponding intervention strategies. Bioinformatics analysis has revealed that growth differentiation factor 15 (GDF15) is highly expressed in HCC and is closely related to poor prognosis of HCC patients. The previous study revealed that GDF15 can promote immunosuppression in the tumor microenvironment. Therefore, knocking out GDF15 through gene editing could potentially reverse the suppressive tumor immune microenvironment permanently. To deliver the CRISPR/Cas9 system specifically to HCC, nanocapsules (SNC) coated with HCC targeting peptides (SP94) on their surface is utilized. These nanocapsules incorporate disulfide bonds (SNCSS) that release their contents in the tumor microenvironment characterized by high levels of glutathione (GSH). In vivo, the SNCSS target HCC cells, exert a marked inhibitory effect on HCC progression, and promote HCC immunotherapy. Mechanistically, CyTOF analysis showed favorable changes in the immune microenvironment of HCC, immunocytes with killer function increased and immunocytes with inhibitive function decreased. These findings highlight the potential of the CRISPR-Cas9 gene editing system in modulating the immune microenvironment and improving the effectiveness of existing immunotherapy approaches for HCC.

Research progress on the protective effect of hormones and hormone drugs in myocardial ischemia-reperfusion injury.

Ischemic heart disease (IHD) is a condition where the heart muscle does not receive enough blood flow, leading to cardiac dysfunction. Restoring blood flow to the coronary artery is an effective clinical therapy for myocardial ischemia. This strategy helps lower the size of the myocardial infarction and improves the prognosis of patients. Nevertheless, if the disrupted blood flow to the heart muscle is restored within a specific timeframe, it leads to more severe harm to the previously deprived heart tissue. This condition is referred to as myocardial ischemia/reperfusion injury (MIRI). Until now, there is a dearth of efficacious strategies to prevent and manage MIRI. Hormones are specialized substances that are produced directly into the circulation by endocrine organs or tissues in humans and animals, and they have particular effects on the body. Hormonal medications utilize human or animal hormones as their active components, encompassing sex hormones, adrenaline medications, thyroid hormone medications, and others. While several studies have examined the preventive properties of different endocrine hormones, such as estrogen and hormone analogs, on myocardial injury caused by ischemia-reperfusion, there are other hormone analogs whose mechanisms of action remain unexplained and whose safety cannot be assured. The current study is on hormones and hormone medications, elucidating the mechanism of hormone pharmaceuticals and emphasizing the cardioprotective effects of different endocrine hormones. It aims to provide guidance for the therapeutic use of drugs and offer direction for the examination of MIRI in clinical therapy.

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

Islr regulates satellite cells asymmetric division through the SPARC/p-ERK1/2 signaling pathway.

Satellite cells (SCs) are adult muscle stem cells responsible for muscle regeneration after acute and chronic muscle injuries. The balance between stem cell self-renewal and differentiation determines the kinetics and efficiency of skeletal muscle regeneration. This study assessed the function of Islr in SC asymmetric division. The deletion of Islr reduced muscle regeneration in adult mice by decreasing the SC pool. Islr is pivotal for SC proliferation, and its deletion promoted the asymmetric division of SCs. A mechanistic search revealed that Islr bound to and degraded secreted protein acidic and rich in cysteine (SPARC), which activated p-ERK1/2 signaling required for asymmetric division. These findings demonstrate that Islr is a key regulator of SC division through the SPARC/p-ERK1/2 signaling pathway. These data provide a basis for treating myopathy.

A c-di-GMP signaling module controls responses to iron in Pseudomonas aeruginosa.

Cyclic dimeric guanosine monophosphate (c-di-GMP) serves as a bacterial second messenger that modulates various processes including biofilm formation, motility, and host-microbe symbiosis. Numerous studies have conducted comprehensive analysis of c-di-GMP. However, the mechanisms by which certain environmental signals such as iron control intracellular c-di-GMP levels are unclear. Here, we show that iron regulates c-di-GMP levels in Pseudomonas aeruginosa by modulating the interaction between an iron-sensing protein, IsmP, and a diguanylate cyclase, ImcA. Binding of iron to the CHASE4 domain of IsmP inhibits the IsmP-ImcA interaction, which leads to increased c-di-GMP synthesis by ImcA, thus promoting biofilm formation and reducing bacterial motility. Structural characterization of the apo-CHASE4 domain and its binding to iron allows us to pinpoint residues defining its specificity. In addition, the cryo-electron microscopy structure of ImcA in complex with a c-di-GMP analog (GMPCPP) suggests a unique conformation in which the compound binds to the catalytic pockets and to the membrane-proximal side located at the cytoplasm. Thus, our results indicate that a CHASE4 domain directly senses iron and modulates the crosstalk between c-di-GMP metabolic enzymes.

CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20.

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.

Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

A self-assembling peptide inhibits the growth and function of fungi via a wrapping strategy.

Fungal infections contribute substantially to human morbidity and mortality. A particular concern is the high rate of mortality associated with invasive fungal infections, which often exceeds 50.0% despite the availability of several antifungal drugs. Herein, we show a self-assembling antifungal peptide (AFP), which is able to bind to chitin on the fungal cell wall and in situ form AFP nanofibers, wrapping fungi. As a result, AFP limits the proliferation of fungi, slows down the morphological transformation of biphasic fungi, and inhibits the adhesion of fungi to host cells and the formation of biofilms. Compared to the broad-spectrum antifungal fluconazole, AFP achieved a comparable inhibitory effect (MIC50 = 3.5 µM) on fungal proliferation. In addition, AFP significantly inhibited the formation of fungal biofilms with the inhibition rate of 69.6% at 1 µM, better than fluconazole (17.2% at 1 µM). In a skin infection model of mice, it was demonstrated that AFP showed significantly superior efficacy to fluconazole. In the systemic candidiasis mouse model, AFP showed similar efficacy to first-line antifungal amphotericin B (AmpB) and anidulafungin (AFG). This study provides a promising wrapping strategy for anti-fungal infection.

Chameleon-like Anammox Bacteria for Surface Color Change after Suffering Starvation.

Bacteria are often exposed to long-term starvation during transportation and storage, during which a series of enzymes and metabolic pathways are activated to ensure survival. However, why the surface color of the bacteria changes during starvation is still not well-known. In this study, we found black anammox consortia suffering from long-term starvation contained 0.86 mmol gVSS-1 cytochrome c, which had no significant discrepancy compared with the red anammox consortia (P > 0.05), indicating cytochrome c was not the key issue for chromaticity change. Conversely, we found that under starvation conditions cysteine degradation is an important metabolic pathway for the blackening of the anammox consortia for H2S production. In particular, anammox bacteria contain large amounts of iron-rich nanoparticles, cytochrome c, and other iron-sulfur clusters that are converted to produce free iron. H2S combines with free iron in bacteria to form Fe-S compounds, which eventually exist stably as FeS2, mainly in the extracellular space. Interestingly, FeS2 could be oxidized by air aeration, which makes the consortia turn red again. The unique self-protection mechanism makes the whole consortia appear black, avoiding inhibition by high concentrations of H2S and achieving Fe storage. This study expands the understanding of the metabolites of anammox bacteria as well as the bacterial survival mechanism during starvation.

Binding-induced fibrillogenesis peptide inhibits RANKL-mediated osteoclast activation against osteoporosis.

Osteoporosis is primarily driven by an imbalance between bone resorption and formation, stemming from enhanced osteoclast activity during bone remodeling. At the crux of this mechanism lies the pivotal RANK-RANKL-OPG axis. In our study, we designed two binding-induced fibrillogenesis (BIF) peptides, namely BIFP and BIFY, targeting RANK and RANKL, respectively. These BIF peptides, with distinct hydrophilic and hydrophobic characteristics, assemble into nanoparticles (NPs) in aqueous solution. Through specific ligand-receptor interactions, these NPs efficiently target and bind to specific proteins, resulting in the formation of fibrous networks that effectively inhibit the RANK-RANKL associations. Experiments have confirmed the potent inhibitory effects of peptides on both osteoclast differentiation and function. Compared with the +RANKL controls, BIFP and BIFY demonstrated a more remarkable reduction in tartrate resistant acid phosphatase (TRAP)-positive cells, achieving an impressive decline of 82.8% and 70.7%, respectively. Remarkably, the administration of BIFP led to a substantial reduction in bone resorption pit area by 17.4%, compared to a significant increase of 92.4% in the +RANKL groups. In vivo experiments on an ovariectomized mouse model demonstrated that the BIFP treated group exhibited an impressive 2.6-fold elevation in bone mineral density and an astounding 4.0-fold enhancement in bone volume/total volume as against those of the PBS-treated group. Overall, BIF peptides demonstrate remarkable abilities to impede osteoclast differentiation, presenting promising prospects for the treatment of osteoporosis.

In vitro fatigue behavior and in vivo osseointegration of the auxetic porous bone screw.

The incidence of screw loosening, migration, and pullout caused by the insufficient screw-bone fixation stability is relatively high in clinical practice. To solve this issue, the auxetic unit-based porous bone screw (AS) has been put forward in our previous work. Its favorable auxetic effect can improve the primary screw-bone fixation stability after implantation. However, porous structure affected the fatigue behavior and in vivo longevity of bone screw. In this study, in vitro fatigue behaviors and in vivo osseointegration performance of the re-entrant unit-based titanium auxetic bone screw were studied. The tensile-tensile fatigue behaviors of AS and nonauxetic bone screw (NS) with the same porosity (51%) were compared via fatigue experiments, fracture analysis, and numerical simulation. The in vivo osseointegration of AS and NS were compared via animal experiment and biomechanical analysis. Additionally, the effects of in vivo dynamic tensile loading on the osseointegration of AS and NS were investigated and analyzed. The fatigue strength of AS was approximately 43% lower while its osseointegration performance was better than NS. Under in vivo dynamic tensile loading, the osseointegration of AS and NS both improved significantly, with the maximum increase of approximately 15%. Preferrable osseointegration of AS might compensate for the shortage of fatigue resistance, ensuring its long-term stability in vivo. Adequate auxetic effect and long-term stability of the AS was supposed to provide enough screw-bone fixation stability to overcome the shortages of the solid bone screw, developing the success of surgery and showing significant clinical application prospects in orthopedic surgery. STATEMENT OF SIGNIFICANCE: This research investigated the high-cycle fatigue behavior of re-entrant unit-based auxetic bone screw under tensile-tensile cyclic loading and its osseointegration performance, which has not been focused on in existing studies. The fatigue strength of auxetic bone screw was lower while the osseointegration was better than non-auxetic bone screw, especially under in vivo tensile loading. Favorable osseointegration of auxetic bone screw might compensate for the shortage of fatigue resistance, ensuring its long-term stability and longevity in vivo. This suggested that with adequate auxetic effect and long-term stability, the auxetic bone screw had significant application prospects in orthopedic surgery. Findings of this study will provide a theoretical guidance for design optimization and clinical application of the auxetic bone screw.

Rac GTPase activating protein 1 promotes the glioma growth by regulating the expression of MCM3.

Glioma is the most common tumor of the nervous system. The diffuse growth and proliferation of glioma poses great challenges for its treatment. Here, Transcriptomic analysis revealed that Rac GTPase activating protein 1 (RACGAP1) is highly expressed in glioma. RACGAP1 has been shown to play an important role in the malignant biological progression of a variety of tumors. However, the underlying role and mechanism in glioma remain poorly understood. By using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunohistochemistry and Orthotopic mouse xenografts, we confirmed that knockdown of RACGAP1 impeded cell proliferation in glioma and prolonged the survival of orthotopic mice. Interestingly, we also found that inhibiting the expression of RACGAP1 reduced the expression of minichromosome maintenance 3 (MCM3) through RNA-seq and rescue assay, while Yin Yang 1 (YY1) transcriptionally regulated RACGAP1 expression. Furthermore, T7 peptide-decorated exosome (T7-exo) is regard as a promising delivery modality for targeted therapy of glioma, and the T7-siRACGAP1-exo significantly improved the survival time of glioma bearing mice. These results suggested that targeting RACGAP1 may be a potential strategy for glioma therapy.

Changes in Drug Clinical Trials of Thyroid Diseases in China, 2009-2022.

Objective: The incidence rate of thyroid diseases increased worldwide. This study aims to overview the changing landscape of drug clinical trials on thyroid disease during 2009-2022. Methods: The detailed information of thyroid disease drug trials registered on the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform for Drug Clinical Studies was searched and collected. The thyroid drug clinical trials were analyzed by the characteristics, time trends, indications, and geographical distribution. Results: Sixty-five thyroid disease drug clinical trials were launched from 2009 to 2022 in China, which included 21 trials in nontumorous thyroid disease and 44 trials in thyroid carcinoma. The number of registered trials of thyroid diseases including thyroid carcinoma and nontumorous thyroid disease increased steadily from 2009 to 2020. Bioequivalence studies accounted for the largest proportion (32[49.2%]), while phase I and Phase II studies both only accounted for 18.5% (12/65). A significant difference was observed in the trials phase, and randomization between thyroid carcinoma and nontumorous thyroid disease. In terms of clinical indications and drug mechanisms, the number of trials in multi-target tyrosine kinase inhibitors for thyroid carcinoma (n=35) ranked first, followed by thyroid hormone for hypothyroidism (n=7), thyrotropin for thyroid carcinoma (n=6). Sixty-five trials were led by 36 principal investigator (PI) units, and more than 30% of PI-leading units were located in Shanghai (n=7) and Beijing (n=4). Conclusion: During the past 13 years, the development of thyroid diseases drugs trials has achieved certain progress in thyroid carcinoma, especially the molecular targeted therapy, yet the development of drug trials on nontumorous thyroid disease was very slow.

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma.

Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an in vivo loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood-brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.

A Biomimetic Peptide Functions as Specific Extracellular Matrix for Quiescence of Stem Cells against Intervertebral Disc Degeneration.

Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.

Molecular Imaging for Early-Stage Disease Diagnosis.

With the development of cellular biology, molecular biology, and other subjects, targeted molecular probe was combined with medical imaging technologies to launch a new scientific discipline of molecular imaging that is a research discipline to visualize, characterize, and analyze biological process at the cellular and molecular levels for real-time tracking and precision therapy, also termed as the medical imaging in the twenty-first century. An array of imaging techniques has been developed to image specific targets of living cells or tissues by molecular probes, including optical molecular imaging (OI), magnetic resonance molecular imaging, ultrasound (US) molecular imaging, nuclear medicine molecular imaging, X-ray molecular imaging, and multi-mode molecular imaging. These imaging techniques make the early diagnosis of various diseases possible by means of visualization of gene expression, interactions between proteins, signal transduction, cell metabolism, cell traces, and other physiological or pathological processes in the living system, which bridge the gap between molecular biology and clinical medicine. This chapter will lay the emphasis on the early-stage diagnosis of fatal diseases, such as malignant tumors, cardio- or cerebrovascular diseases, digestive system disease, central nervous system disease, and other diseases employing molecular imaging in a real-time visualized manner.