Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Chemical constituents with antioxidant activity from the branches and leaves of Hultholia mimosoides.

Four undescribed homoisoflavanoids (1-4), one homoflavonoid (5), ten dibenzoxocin derivatives (6a-10a and 6b-10b), one dibenzoxocin-derived phenolic compound (11), one diterpenoid (13), three aliphatic dicarboxylic acid derivatives (14-16), together with the known diterpenoid 12-O-ethylneocaesalpin B (12) were obtained from the branches and leaves of Hultholia mimosoides. Their structures were elucidated by extensive spectroscopic techniques. Notably, each of the dibenzoxocins 6-10 existed as a pair of interconvertible atropisomers and the conformation for these compounds was clarified by NMR and ECD analyses. Protosappanin F (11) was a previously undescribed dibenzoxocin-derived compound in which one of the benzene rings was hydrogenated to a polyoxygenated cyclohexane ring and an ether linkage was established between C-6 and C-12a. The isolated polyphenols were tested for induction of quinone reductase and compounds 3 and 8 showed potent QR-inducing activity in Hepa-1c1c7 cells.

Comprehensive analysis of m6A methylome alterations after azacytidine plus venetoclax treatment for acute myeloid leukemia by nanopore sequencing.

N6 adenosine methylation (m6A), one of the most prevalent internal modifications on mammalian RNAs, regulates RNA transcription, stabilization, and splicing. Growing evidence has focused on the functional role of m6A regulators on acute myeloid leukemia (AML). However, the global m6A levels after azacytidine (AZA) plus venetoclax (VEN) treatment in AML patients remain unclear. In our present study, bone marrow (BM) sample pairs (including pre-treatment [AML] and post-treatment [complete remission (CR)] samples) were harvested from three AML patients who had achieved CR after AZA plus VEN treatment for Nanopore direct RNA sequencing. Notably, the amount of m6A sites and the m6A levels in CR BMs was significantly lower than those in the AML BMs. Such a significant reduction in the m6A levels was also detected in AZA-treated HL-60 cells. Thirteen genes with decreased m6A and expression levels were identified, among which three genes (HPRT1, SNRPC, and ANP32B) were closely related to the prognosis of AML. Finally, we speculated the mechanism via which m6A modifications affected the mRNA stability of these three genes. In conclusion, we illustrated for the first time the global landscape of m6A levels in AZA plus VEN treated AML (CR) patients and revealed that AZA had a significant demethylation effect at the RNA level in AML patients. In addition, we identified new biomarkers for AZA plus VEN-treated AML via Nanopore sequencing technology in RNA epigenetics.

Prediction significance of autophagy-related genes in survival probability and drug resistance in diffuse large B-cell lymphoma.

BACKGROUND/AIMS: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has significant prognostic heterogeneity. This study aimed to generate a prognostic prediction model based on autophagy-related genes for DLBCL patients. METHODS: Utilizing bioinformatics techniques, we analyzed the clinical information and transcriptome data of DLBCL patients from the Gene Expression Omnibus (GEO) database. Through unsupervised clustering, we identified new autophagy-related molecular subtypes and pinpointed differentially expressed genes (DEGs) between these subtypes. Based on these DEGs, a prognostic model was constructed using Cox and Lasso regression. The effectiveness, accuracy, and clinical utility of this prognostic model were assessed using numerous independent validation cohorts, survival analyses, receiver operating characteristic (ROC) curves, multivariate Cox regression analysis, nomograms, and calibration curves. Moreover, functional analysis, immune cell infiltration, and drug sensitivity analysis were performed. RESULTS: DLBCL patients with different clinical characterizations (age, molecular subtypes, ECOG scores, and stages) showed different expression features of autophagy-related genes. The prediction model was constructed based on the eight autophagy-related genes (ADD3, IGFBP3, TPM1, LYZ, AFDN, DNAJC10, GLIS3, and CCDC102A). The prognostic nomogram for overall survival of DLBCL patients incorporated risk level, stage, ECOG scores, and molecular subtypes, showing excellent agreement between observed and predicted outcomes. Differences were noted in the proportions of immune cells (native B cells, Treg cells, CD8+ T cell, CD4+ memory activated T cells, gamma delta T cells, macrophages M1, and resting mast cells) between high-risk and low-risk groups. LYZ and ADD3 exhibited correlations with drug resistance to most chemotherapeutic drugs. CONCLUSIONS: This study established a novel prognostic assessment model based on the expression profile of autophagy-related genes and clinical characteristics of DLBCL patients, explored immune infiltration and predicted drug resistance, which may guide precise and individualized immunochemotherapy regimens.

Validation and modification of simplified Geriatric Assessment and Elderly Prognostic Index: Effective tools for older patients with diffuse large B-cell lymphoma.

Geriatric assessment can aid in optimizing treatment strategies and supportive interventions for older patients with diffuse large B-cell lymphoma (DLBCL). Fondazione Italiana Linformi has recently introduced novel geriatric assessment tools, simplified Geriatric Assessment (sGA) and Elderly Prognostic Index (EPI), aimed at tailoring the treatment and predicting the outcomes for older patients with DLBCL. The objectives of this study are the validation and possible modification of the sGA and EPI in China. In the study, both sGA and EPI demonstrated the predictive capabilities for overall survival (OS) and early mortality (both p < 0.05) in older individuals with DLBCL. Albumin, serving as an independent predictive biomarker for OS (p = 0.006), was utilized to adjust the measurements, resulting in the establishment of sGA-A and EPI-A. The sGA-A effectively addressed the shortcomings of the sGA and EPI in predicting PFS and surpassed them in predicting OS and early mortality. Nevertheless, there is insufficient evidence to support the use of sGA and EPI as treatment guidance tools. In conclusion, the modified sGA-A model proved to be a successful instrument for geriatric assessment of older patients with DLBCL.

Changing epidemiology, microbiology and mortality of bloodstream infections in patients with haematological malignancies before and during SARS-CoV-2 pandemic: a retrospective cohort study.

OBJECTIVE: This study was to explore the changes in bacterial bloodstream infection (BSI) in patients with haematological malignancies (HMs) before and during SARS-CoV-2 pandemic. DESIGN: Retrospective cohort study between 2018 and 2021. SETTING: The largest haematological centre in southern China. RESULTS: A total of 599 episodes of BSI occurring in 22 717 inpatients from January 2018 to December 2021 were analysed. The frequencies of the total, Gram-negative and Gram-positive BSI before and during the pandemic were 2.90% versus 2.35% (p=0.011), 2.49% versus 1.77% (p<0.001) and 0.27% versus 0.44% (p=0.027), respectively. The main isolates from Gram-negative or Gram-positive BSI and susceptibility profiles also changed. The 30-day mortality caused by BSI was lower during the pandemic (21.1% vs 14.3%, p=0.043). Multivariate analysis revealed that disease status, pulmonary infection and shock were independent predictors of 30-day mortality. CONCLUSION: Our data showed that the incidence of total and Gram-negative organisms BSI decreased, but Gram-positive BSI incidence increased in patients with HMs during the pandemic along with the changes of main isolates and susceptibility profiles. Although the 30-day mortality due to BSI was lower during the pandemic, the new infection prevention strategy should be considered for any future pandemics.

Low-dose decitabine for previously untreated acute myeloid leukemia ineligible for intensive chemotherapy aged 65 years or older: a prospective study based on comprehensive geriatric assessment.

Background: The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy. Objectives: We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment. Design: We performed a prospective, multicenter, open-label, and non-randomized study. Methods: Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m2 for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity. Results: Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65-90) years. The median follow-up time was 22.2 (range, 4.6-38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment. Conclusion: In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.

Long-term outcomes of second-line versus later-line zanubrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: An updated pooled analysis.

BACKGROUND: We previously reported results of a pooled analysis of two zanubrutinib studies in relapsed or refractory (R/R) MCL showing better survival outcomes when zanubrutinib is used in second-line versus later-line. Here, we present an updated pooled analysis with a longer follow-up of 35.2 months. METHODS: Data were pooled from two studies-BGB-3111-AU-003 (NCT02343120) and BGB-3111-206 (NCT03206970) of zanubrutinib in R/R MCL. The patients were divided into two groups based on the treatment line of zanubrutinib: the second-line and the later-line group. The inverse propensity score weighting method was used to balance the baseline covariates between the groups. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), PFS, and OS rates, objective response rate (ORR), duration of response (DOR), and safety. RESULTS: Among 112 pooled patients, 41 (36.6%) patients received zanubrutinib as second-line and 71 (63.4%) patients as later-line therapy. After weighting, OS was significantly improved in the second-line versus later-line group (HR, 0.459 [95% CI: 0.215, 0.98]; p = 0.044) with median OS not estimable in both groups. The PFS was similar between the two groups (HR, 0.78 [95% CI: 0.443, 1.373]; p = 0.389) but with numerically longer median PFS in the second-line versus later-line group (27.8 vs. 22.1 months). ORR was numerically higher in the second-line versus later-line (88.6% vs. 85.7%), and DOR was similar between the two groups (25.2 vs. 25.1 months). Zanubrutinib showed a similar safety profile in both groups. CONCLUSION: Zanubrutinib in second-line treatment was associated with significantly improved OS compared with later-line treatment of R/R MCL.

The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase.

BACKGROUND: KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell carcinoma (ccRCC) remains poorly understood. METHODS: KSRP expression was detected by a ccRCC tissue microarray and evaluated by an in silico analysis. Cell loss-of-function and gain-of-function, colony-formation, anoikis, and transwell assays, and an orthotopic bioluminescent xenograft model were conducted to determine the functional role of KRSP in ccRCC progression. Micro (mi)RNA and complementary (c)DNA microarrays were used to identify downstream targets of KSRP. Western blotting, quantitative real-time polymerase chain reaction, and promoter- and 3-untranslated region (3'UTR)-luciferase reporter assays were employed to validate the underlying mechanisms of KSRP which aggravate progression of ccRCC. RESULTS: Our results showed that dysregulated high levels of KSRP were correlated with advanced clinical stages, larger tumor sizes, recurrence, and poor prognoses of ccRCC. Neural precursor cell-expressed developmentally downregulated 4 like (NEDD4L) was identified as a novel target of KSRP, which can reverse the protumorigenic and prometastatic characteristics as well as epithelial-mesenchymal transition (EMT) promotion by KSRP in vitro and in vivo. Molecular studies revealed that KSRP can decrease NEDD4L messenger (m)RNA stability via inducing mir-629-5p upregulation and directly targeting the AU-rich elements (AREs) of the 3'UTR. Moreover, KSRP was shown to transcriptionally suppress NEDD4L via inducing the transcriptional repressor, Wilm's tumor 1 (WT1). In the clinic, ccRCC samples revealed a positive correlation between KSRP and mesenchymal-related genes, and patients expressing high KSRP and low NEDD4L had the worst prognoses. CONCLUSION: The current findings unveil novel mechanisms of KSRP which promote malignant progression of ccRCC through transcriptional inhibition and post-transcriptional destabilization of NEDD4L transcripts. Targeting KSRP and its pathways may be a novel pharmaceutical intervention for ccRCC.

IGH rod-like tracer: An AlphaFold2 structural similarity extraction-based predictive biomarker for MRD monitoring in pre-B-ALL.

Sequence variation resulting from the evolution of IGH clones and immunophenotypic drift makes it difficult to track abnormal B cells in children with precursor B cell acute lymphoblastic leukemia (pre-B-ALL) by flow cytometry, qPCR, or next-generation sequencing (NGS). The V-(D)-J regions of immunoglobulin and T cell receptor of 47 pre-B-ALL samples were sequenced using the Illumina NovaSeq platform. The IGH rod-like tracer consensus sequence was extracted based on its rod-like alpha-helices structural similarity predicted by AlphaFold2. Additional data from published 203 pre-B-ALL samples were applied for validation. NGS-IGH (+) patients with pre-B-ALL had a poor prognosis. Consistent CDR3-coded protein structures in NGS-IGH (+) samples could be extracted as a potential follow-up marker for pre-B-ALL children during treatment. IGH rod-like tracer from quantitative immune repertoire sequencing may serve as a class of biomarker with significant predictive values for the dynamic monitoring of MRD in pre-B-ALL children.

Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed or refractory mantle cell lymphoma.

We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients.

Charge transfer and vacancy engineering of Fe2O3 nanoparticle catalysts for highly selective N2 reduction towards NH3 synthesis.

The development of electrocatalysts for N2 reduction reaction (NRR) is significant for scalable and renewable NH3 synthesis, but calls for a technology innovation to overcome the specific problems of low efficiency and poor selectivity. Herein, we prepare a core-shell nanostructure by coating polypyrrole (PPy) onto sulfur-doped iron oxide nanoparticles (denoted as S-Fe2O3@PPy) as the highly selective and durable electrocatalysts for NRR under ambient conditions. Sulfur doping and PPy coating remarkably improve the charge transfer efficiency of S-Fe2O3@PPy, and the interactions between PPy and Fe2O3 nanoparticles produce abundant oxygen vacancies as active sites for NRR. This catalyst achieves an NH3 production rate of 22.1 µg h-1 mgcat-1 and a very-high Faradic efficiency of 24.6%, surpassing other Fe2O3 based NRR catalysts. Density functional theory calculations show that the S-coordinated iron site can successfully activate the N2 molecule and optimize the energy barrier during the reduction process, resulting in a small theoretical limiting potential.

Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China.

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0-3.4; OS, 54.9 months vs. NR, p<0.001, HR=3.2, 95% CI 1.5-7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival.

Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.

The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood-brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases.

Blockade of trans PD-L1 interaction with CD80 augments antitumor immunity.

PD-L1 has two receptors: PD-1 and CD80. Previous reports assumed that PD-L1 and CD80 interacted in trans, but recent reports showed that only cis PD-L1/CD80 interactions existed, and prevention of cis PD-L1/CD80 interactions on antigen-presenting cells (APCs) reduced antitumor immunity via augmenting PD-L1/PD-1 and CD80/CTLA4 interactions between T and APCs. Here, using tumor-bearing mice capable of cis and trans or trans only PD-L1/CD80 interactions, we show that trans PD-L1/CD80 interactions do exist between tumor and T cells, and the effects of trans PD-L1/CD80 interactions require tumor cell expression of MHC-I and T cell expression of CD28. The blockade of PD-L1/CD80 interactions in mice with both cis and trans interactions or with only trans interactions augments antitumor immunity by expanding IFN-γ-producing CD8+ T cells and IFN-γ-dependent NOS2-expressing tumor-associated macrophages. Our studies indicate that although cis and trans PD-L1/CD80 interactions may have opposite effects on antitumor immunity, the net effect of blocking PD-L1/CD80 interactions in vivo augments CD8+ T cell-mediated antitumor immunity.

Lycium barbarum Ameliorates Neural Damage Induced by Experimental Ischemic Stroke and Radiation Exposure.

Ischemic stroke and cranial radiotherapy may induce brain inflammatory response, oxidative stress, apoptosis and neuronal loss, and impairment of neurogenesis. Lycium barbarum has anti-oxidation, anti-inflammatory, anti-tumor and anti-aging properties, may produce both neuroprotective and radioprotective effects. In this narrative review paper, we described the neuroprotective effect of Lycium barbarum in different animal models of experimental ischemic stroke and limited studies in irradiated animal models. Relevant molecular mechanisms are also summarized. It has been shown that in experimental ischemic stroke models, Lycium barbarum produces neuroprotective effects by modulating neuroinflammatory factors such as cytokines and chemokines, reactive oxygen species, and neurotransmitter and receptor systems. In irradiation animal models, Lycium barbarum prevents radiation-induced loss of hippocampal interneurons. Given its minimal side-effects, these preclinical studies suggest that Lycium barbarum may be a promising radio-neuro-protective drug that can be used as an adjunct treatment to radiotherapy for brain tumor and in the treatment of ischemic stroke. At molecular levels, Lycium barbarum may regulate PI3K/Akt/GSK-3ß, PI3K/Akt/mTOR, PKCε/Nrf2/HO-1, keap1-Nrf2/HO-1, and NR2A and NR2B receptor- related signal transduction pathways to produce neuroprotective effects.

Proteoglycan SPOCK1 as a Poor Prognostic Marker Promotes Malignant Progression of Clear Cell Renal Cell Carcinoma via Triggering the Snail/Slug-MMP-2 Axis-Mediated Epithelial-to-Mesenchymal Transition.

Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein levels were observed in ccRCC tissues compared to normal tissues and correlated with advanced clinical stages, larger tumor sizes, and lymph node and distal metastases. Knockdown and overexpression of SPOCK1 in ccRCC cells led to decreased and increased cell clonogenic and migratory/invasive abilities in vitro as well as lower and higher tumor growth and invasion in vivo, respectively. Mechanistically, the gene set enrichment analysis (GSEA) database was used to identify the gene set of epithelial-to-mesenchymal transition (EMT) pathways enriched in ccRCC samples with high SPOCK1 expression. Further mechanistic investigations revealed that SPOCK1 triggered the Snail/Slug-matrix metalloproteinase (MMP)-2 axis to promote EMT and cell motility. Clinical ccRCC samples revealed SPOCK1 to be an independent prognostic factor for overall survival (OS), and positive correlations of SPOCK1 with MMP-2 and mesenchymal-related gene expression levels were found. We observed that patients with SPOCK1high/MMP2high tumors had the shortest OS times compared to others. In conclusion, our findings reveal that SPOCK1 can serve as a useful biomarker for predicting ccRCC progression and prognosis, and as a promising target for treating ccRCC.