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Abstract Background Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). Conclusions RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

ObjectiveThis systematic review evaluates the impact of exercise intervention in MCI patients and discusses the potential neural mechanisms.MethodsA systematic search and screening of relevant literature was conducted in English and Chinese databases. Based on predefined keywords and criteria, 24 articles were assessed and analyzed.ResultsStructurally, a significant increase was observed in the hippocampal and gray matter volumes of MCI patients following exercise intervention, with a trend of improvement in cortical thickness and white matter integrity. Functionally, after the exercise intervention, there were significant changes in the local spontaneous brain activity levels, cerebral blood flow, and functional connectivity during rest and memory encoding and retrieval tasks in MCI patients.ConclusionExercise may contribute to delaying neurodegenerative changes in brain structure and function in patients with MCI. However, the underlying neural mechanisms require further research.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023482419.

Previous studies have shown that histone deacetylase 6 (HDAC6) plays critical roles in many cellular processes related to cancer. However, its biological roles in the development of melanoma remain unexplored. Our aim was to investigate whether HDAC6 has a biological role in human melanoma development and to understand its underlying mechanism. In the present study, HDAC6 expression was up-regulated in melanoma tissues and cell lines. Knockdown of HDAC6 significantly inhibited the proliferation and colony formation ability of A375.S2 cells, promoted cell arrest at G0/G1 phase and apoptosis. Additionally, western blotting assay showed that HDAC6 silencing suppressed Bcl-2 level and enhanced Bax level, then activated caspase-9 and caspase-3, and further activated the release of cytochrome c from mitochondria to cytoplasm, finally induced cell apoptosis involving the mitochondrial pathway. Knockdown of HDAC6 triggered a significant generation of ROS and disruption of mitochondrial membrane potential (MMP). Furthermore, ROS inhibitor, NAC reduced HDAC6 siRNA-induced ROS production, and blocked HDAC6 siRNA-induced loss of MMP and apoptosis. NAC also significantly blocked HDAC6 siRNA-induced mtDNA copy number decrease and mitochondrial biogenesis and degradation imbalance. In conclusion, the results showed that knockdown of HDAC6 induced apoptosis in human melanoma A375.S2 cells through a ROS-dependent mitochondrial pathway.

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and continues to have a significant impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, which is primarily responsible for the host immune response upon infection. Here we present the preclinical studies of a broadly protective SARS-CoV-2 subunit vaccine developed from our trimer domain platform using the Delta spike protein, from antigen design through purification, vaccine evaluation and manufacturability. The pre-fusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. Immunogenicity studies have shown that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous viral challenge. Neutralizing antibodies induced by this vaccine show cross-reactivity against the ancestral WA1, Delta and several Omicrons, including BA.5.2. The formulated PF-D Trimer is stable for up to six months without refrigeration. The Trimer Domain platform was proven to be a key technology in the rapid production of PF-D-Trimer vaccine and may be crucial to accelerate the development and accessibility of updated versions of SARS-CoV-2 vaccines.

A lactosylated and AIE-active multifunctional photosensitizer (Lac-TR) was synthesized. Lac-TR can self-assemble into fluorescent nanoparticles (Lac-TRs) to achieve fluorescence self-reporting during photodynamic therapy and induce pyroptosis under both normoxia and hypoxia to kill HepG2 cells. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine whether serum-and glucocorticoid-inducible kinase1 (SGK1) activation-dependent histone deacetylase 4 (HDAC4) phosphorylation, nucleocytoplasmic trafficking, and subsequent regulation of high-mobility group protein box 1 (HMGB1) expression are involved in type 2 diabetic neuropathic pain (DNP). Methods: The type 2 diabetic neuropathic pain model was established in rats by feeding them with a high-fat and high-sugar diet for 8 weeks and then fasting them for 12 h, followed by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg). SGK1 was inhibited in the spinal cord by intrathecal administration of the SGK1 inhibitor GSK-650394. Results: The present study revealed that pSGK1/tSGK1 was persistently upregulated in the spinal cord of rats with type-2 DNP. The downregulation of pSGK1/tSGK1 through the intrathecal injection of the SGK1 inhibitor GSK-650394 significantly ameliorated the pain hypersensitivity, relieved the abnormal expression of pHDAC4/tHDAC4 and HMGB1, and affected HDAC4 nucleocytoplasmic trafficking in DNP rats. Conclusion: Our data suggest that SGK1 in the spinal cord modulates type-2 DNP by regulating the HDAC4/HMGB1 pathway. [ABSTRACT FROM AUTHOR]

Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near‐infrared light‐triggered photolysis process of current photocage is largely singlet oxygen (1O2)‐dependent and lack of compatibility with other reactive oxygen species (ROS)‐activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT‐LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY‐TPE fluorophore via the superoxide anion radical (O2−⋅)‐cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT‐LRC could be self‐assembled into aggregation‐induced emission (AIE)‐active nanoparticles (BT‐LRCs) owing to the regulation of carbohydrate‐carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT‐LRCs could simultaneously generate abundant O2−⋅ through the aggregation modulated by lactose interactions, and DNA‐damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor‐bearing mice. Furthermore, the inherent AIE property of BT‐LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real‐time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy. [ABSTRACT FROM AUTHOR]

Most fluorogens with aggregation-induced emission (AIE) characteristics are hydrophobic and most common sugars are hydrophilic and naturally nontoxic. The combination of AIEgens and sugars can construct glycosyl AIEgens with the advantages of good water-solubility, low fluorescent background and satisfactory biocompatibility. Based on the specific reaction or binding with analytes to change the conjugate system or restrict intramolecular motions, glycosyl AIEgens can be used as powerful tools for detecting bioactive molecules or imaging living cells. In this feature article, we summarize recent advances in sugar-based AIE luminogens and their applications in biosensing and imaging. The sugar units could significantly increase the solubility, biocompatibility, target activity, and chemical modifying capacity and often decrease the background fluorescence of the AIE probes. Corresponding studies not only expand the application fields of AIEgens but also provide effective tools for broad carbohydrate research. [ABSTRACT FROM AUTHOR]

To analyze the influence of professional identity and academic efficacy on the professional attitude of higher vocational nursing students.

Pronounced inflammation after intracerebral hemorrhage (ICH) contributes to secondary brain injury, which seriously affects the prognosis of ICH patients. Fractalkine (FKN)/CX3CR1 pathway may play an important role in regulating inflammatory reactions after ICH. As resident immunocyte in brain, microglia is essential for inflammatory reactions in central nervous system. This study intends to explore the effect of FKN/CX3CR1 pathway on microglia after experimental ICH and its possible mechanisms. In mouse ICH models, FKN and TGF-β1 levels gradually increased and showed a positive correlation, both of which peaked at the third day after ICH model. Compared with ICH only, the ratio of s-FKN/m-FKN, microglia activation, and neuronal apoptosis were all decreased after injecting ADAM10 inhibitor (G1254023X) into the lateral ventricle. The expression of inflammatory factors was increased after stimulation with hemin in BV2 cells. The addition of m-FKN reduced the inflammatory response to a certain extent, and the inhibitor of TGF-β1 could counteract the effect of m-FKN.In conclusion, in mouse ICH model, the expression of FKN is increased, and m-FKN may inhibit the activation of microglia and reduce neuron apoptosis by promoting the expression of TGF-β1.

Morindae officinalis Radix (MOR) is a famous traditional Chinese medicine (TCM) and functional food material for invigorating kidneys and tonifying yang. Processed Morindae officinalis Radix (PMOR) is obtained by steaming MOR. Traditionally, the clinical effects are discrepant between processing and nonprocessing herbal medicines. MOR and PMOR are commonly used in both clinical practice and dietary supplements, and the effect of invigorating kidneys and tonifying yang of PMOR is stronger than MOR. To clarify the overall chemical composition and the difference of MOR and PMOR, a method was developed with an ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). Among the 110 identified components shared by MOR and PMOR, 55 compounds showed significant differences in contents. Among them, the contents of 29 components, including fructooligosaccharides, monotropein, deacetylasperulosidic acid, geniposide, and anthraquinone glycosides, were higher in MOR than in PMOR; the contents of 26 components, including difructose anhydride sucrose, and iridoid glycoside derivatives, were higher in PMOR than in MOR. Difructose anhydrides and iridoid glycoside derivatives were first discovered in PMOR. These results provided a scientific basis for research on the therapeutic material basis of MOR. It would provide a method for the comparison of processing and nonprocessing in Chinese medicines.

Objective. Currently, clinical classification of osteosarcoma cannot accurately predict the survival outcomes and responses to chemo- or immunotherapies. Our goal was to classify osteosarcoma patients into clinical/biological subtypes based on EMT molecules. Methods. This study retrospectively curated the RNA expression profiling of osteosarcoma patients from the TARGET and GSE21257 cohorts. Consensus clustering analyses were conducted in accordance with the expression profiling of prognostic EMT genes derived from univariate analyses. Immunological features were evaluated through immune cell infiltration, immune checkpoint expression, and activity of cancer immunity cycle. Drug sensitivity was estimated with the GDSC database. WGCNA approach was adopted to determine the EMT-derived genes. Following univariate analyses, a multivariate cox regression model was developed and externally verified. Predictive independency was evaluated with uni- and multivariate analyses. GSEA was presented to uncover relevant molecular mechanisms. Results. Prognostic EMT genes across osteosarcoma patients were stratified into distinct subtypes, namely, subtypes A and B. Patients in subtype B presented desirable prognosis, high immune activation, and enhanced sensitivity to cisplatin. Meanwhile, patients in subtype A were more sensitive to gemcitabine. In total, 86 EMT-derived hub genes were determined, and an EMT score was conducted for osteosarcoma prognosis. Following external verification, this EMT score was reliably and independently predictive of patients’ survival outcomes. Additionally, it was positively linked to steroid biosynthesis. Conclusion. Overall, our findings proposed EMT-relevant molecular subtypes and signatures for predicting prognosis and therapeutic responses, contributing to personalized treatment and clinical implication for osteosarcoma.

Abstract Background Migraine is one of the most common neurological disorders that leads to disabilities. However, the conventional drug therapy for migraine might be unsatisfactory at times. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibody (CGRP mAb) for the preventive treatment of episodic migraine, and provide high-quality clinical evidence for migraine therapy. Methods A systematic electronic database search was conducted to identify the potentially relevant studies. Two independent authors performed data extraction and quality appraisal. Mean difference (MD) and risk ratio (RR) were pooled for continuous and dichotomous data, respectively. The significance levels, weighted effect sizes and homogeneity of variance were calculated. Results Eleven high-quality randomized control trials that collectively included 4402 patients were included in this meta-analysis. Compared to placebo group, CGRP mAb therapy resulted in a reduction of monthly migraine days [weighted mean difference (WMD) = − 1.44, 95% CI = (− 1.68,− 1.19)] and acute migraine-specific medication days [WMD = − 1.28, 95% CI = (− 1.66,− 0.90)], with an improvement in 50% responder rate [RR = 1.51, 95% CI = (1.37,1.66)]. In addition, the adverse events (AEs) and treatment withdrawal rates due to AEs were not significantly different between CGRP mAb and placebo groups. Similar efficacy and safety results were obtained for erenumab, fremanezumab, and galcanezumab in subgroup analysis. Conclusions The current body of evidence reveals that CGRP mAb is an effective and safe preventive treatment for episodic migraine.