PDCD4 interacting with PIK3CB and CTSZ promotes the apoptosis of multiple myeloma cells.

The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA-binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5' UTR of the apoptosis-related genes PIK3CB, Cathepsin Z (CTSZ), and X-chromosome-linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5' UTRs of PIK3CB and CTSZ. An RNA pull-down assay confirmed binding of the 5' UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5' UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment.

Evaluation and analysis of surgical treatment for single-level or multi-level lumbar degenerative disease based on radiography.

Background: Radiography has a low level of radiation exposure while providing valuable information. Due to its cost effectiveness and widespread availability, the preoperative radiographic imaging examination is a valuable approach for assessing patients with spinal disease. This study aimed to examine the influence of preoperative X-ray evaluation on the surgical treatment of patients with single- or multi-level lumbar degenerative disease (LDD). Methods: A retrospective cohort analysis was conducted of 172 patients diagnosed with LDD who underwent transforaminal lumbar interbody fusion (TLIF) or posterior lumbar interbody fusion (PLIF) surgery between December 2021 and February 2023 at the Shanghai Changzheng Hospital. Various parameters were measured on preoperative radiographs, including the iliac crest height, median iliac angle (MIA), lumbar lordosis (LL), intervertebral facet joint degeneration, lumbosacral angle (LSA), intervertebral foramen height (IFH), and surgical segment. The surgical treatment was evaluated based on the operative time, intraoperative blood loss, and postoperative complications. A correlation analysis and independent sample t-tests were used to assess the relationship between preoperative radiographic variables and surgical treatments. Further, a multivariate linear regression analysis was employed to identify the risk factors affecting the clinical outcomes. Results: The correlation analysis and t-test results showed that the MIA, height of the iliac crest, intervertebral facet joint degeneration, and surgical segment were significantly correlated with the surgical treatments (P<0.05). Specifically, the height of the iliac crest, intervertebral facet joint degeneration, and surgical segment were positively correlated with the surgical treatments. Conversely, the MIA was negatively correlated with the surgical treatments. However, no significant differences were observed between the IFH, LSA, and LL in relation to posterior lumbar surgery (P>0.05). The multiple linear regression analysis showed that the height of the iliac crest, MIA, intervertebral facet joint degeneration, and surgical segment were independent factors affecting the surgical treatments of patients with single- or multi-level LDD. These findings highlight the importance of considering these factors when planning and performing lumbar surgery. Conclusions: The measurements taken from radiographs, including the height of the iliac crest, MIA, intervertebral facet joint degeneration, and surgical segment, demonstrate potential influences on the treatment of single- and multi-level lumbar spine surgery. These variables can be captured in plain film imaging and can provide valuable insights into the surgical procedure and offer guidance for the operation. By analyzing these radiographic measurements, surgeons can gain a better understanding of a patient's condition and tailor the surgical approach accordingly, thus optimizing the outcomes of the surgery.

A retrospective cohort study on the significance of preoperative radiological evaluation of lumbar degenerative diseases for surgical reference.

Background: Radiography has low radiation exposure and the ability to acquire information. Due to its cost-effectiveness and availability, preoperative radiographic imaging examination is considered to be a valuable method to evaluate the condition of patients with spinal disease. The aim of this cohort study is to analyze the impact of evaluating preoperative X-rays on the surgical management of lumbar degenerative diseases (LDD). Methods: We reviewed 49 patients with LDD underwent single-level posterior instrumented lumbar fusion (PILF) between November 2017 and October 2022 in this cohort study. The median iliac angle (MIA), iliac crest height, intervertebral facet joint degeneration, lumbosacral angle (LSA), L5/S1 intervertebral space angle (ISA), intervertebral foramen height (IFH) and intervertebral space height (ISH) were measured on preoperative radiographs. In addition, operative time, intraoperative blood loss and postoperative complications were used to evaluate the surgical management. Correlation analysis was used to determine the correlation between preoperative radiographic presentation and surgical managements. Multivariate linear regression analysis was used for determination of risk factors for surgical management. Results: Correlation analysis showed that the median iliac angle, height of iliac crest, lumbosacral angle and intervertebral facet joint degeneration were significantly correlated with surgical managements (P<0.05). Height of iliac crest, intervertebral facet joint degeneration and lumbosacral angle were positively correlated with surgical management. Meanwhile, MIA was negatively correlated with surgical management. No significant difference was found between the IFH, ISA, ISH and surgical managements in posterior lumbar surgery (P>0.05). After multiple linear regression analysis, height of iliac crest, median iliac angle and intervertebral facet joint degeneration were independent influence factors for the single-level lumbar surgical managements. Conclusions: Some variables measured in radiograph shows that height of iliac crest, median iliac angle and intervertebral facet joint degeneration have a potential influence on surgical managements. The lumbosacral angle was positively associated with surgical management, but it was not statistically significant in multiple linear regression analysis (P>0.05). The above measurements in plain film can reflect the surgical procedure and have some guiding implications for the operation.

Safety and efficacy of PD-1 and PD-L1 inhibitors in relapsed and refractory Hodgkin's lymphoma: a systematic review and meta-analysis of 20 prospective studies.

BACKGROUND: Inhibitors of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been used in the treatment of relapsed and refractory Hodgkin's lymphoma (R/R HL) recently. To further understand the safety and efficacy of PD-1/PD-L1 inhibitors in R/R HL, we conducted this meta-analysis. METHODS: Databases and the Clinical Registration Platforms have been systematically searched for related studies by March 2022. For safety analysis, the incidence and exhibition of any grade and grade 3 or higher adverse effects (AEs) were evaluated. Besides, severe AEs (SAEs), treatment-related deaths, and AEs leading to treatment discontinuation were summarized. The overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), overall survival (OS), and duration of response (DOR) were calculated for efficacy analysis. All processes were implemented mainly through the package Meta and MetaSurv of software R 4.1.2. RESULTS: Overall 20 studies and 1440 patients were enrolled. The pooled incidence of any grade and grade 3 or higher AEs were 92% and 26%, respectively. The pooled ORR, CR rate and PR rate were 79%, 44% and 34%, respectively. The most common AEs were neuropathy (29%), nausea (27%), pyrexia (26%), and leukopenia (25%), and the most common grade 3 or higher AEs included leukopenia (10%), infusion reaction (8%), weight gain (3%), and neutropenia (2.7%). In survival analysis, pembrolizumab monotherapy appeared to perform better compared to nivolumab monotherapy. CONCLUSIONS: PD-1/PD-L1 inhibitors show promising efficacy and tolerable AEs in the treatment of R/R HL.

The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection.

Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.

Identifying the Role of Oxidative Stress-Related Genes as Prognostic Biomarkers and Predicting the Response of Immunotherapy and Chemotherapy in Ovarian Cancer.

Background: Ovarian cancer (OC) is one of the most frequently seen and fatal gynecological malignancies, and oxidative stress (OS) plays a critical role in the development and chemoresistance of OC. Materials and Methods: OS-related genes (OSRGs) were obtained from the Molecular Signatures Database. Besides, gene expression profiles and clinical information from The Cancer Genome Atlas (TCGA) were selected to identify the prognostic OSRGs. Moreover, univariate Cox regression, LASSO, and multivariate Cox regression analyses were conducted sequentially to establish a prognostic signature, which was later validated in three independent Gene Expression Omnibus (GEO) datasets. Next, gene set enrichment analysis (GSEA) and tumor mutation burden (TMB) analysis were performed. Afterwards, immune checkpoint genes (ICGs) and the tumor immune dysfunction and exclusion (TIDE) algorithm, together with IMvigor210 and GSE78220 cohorts, were applied to comprehensively explore the role of OSRG signature in immunotherapy. Further, the CellMiner and Genomics of Drug Sensitivity in Cancer (GDSC) databases were also applied in investigating the significance of OSRG signature in chemotherapy. Results: Altogether, 34 prognostic OSRGs were identified, among which 14 were chosen to establish the most valuable prognostic signature. The Kaplan-Meier (KM) analysis suggested that patients with lower OS-related risk score had better prognosis. The area under the curve (AUC) values were 0.71, 0.76, and 0.85 in 3, 5, and 7 years separately, and the stability of this prognostic signature was confirmed in three GEO datasets. As revealed by GSEA and TMB analysis results, OC patients in low-risk group might have better immunotherapeutic response, which was consistent with ICG expression and TIDE analyses. Moreover, both IMvigor210 and GSE78220 cohorts demonstrated that patients with lower OS-related risk score were more likely to benefit from anti-PD-1/L1 immunotherapy. In addition, the association between prognostic signature and drug sensitivity was explored. Conclusion: According to our results in this work, OSRG signature can act as a powerful prognostic predictor for OC, which contributes to generating more individualized therapeutic strategies for OC patients.

Establishment, immunological analysis, and drug prediction of a prognostic signature of ovarian cancer related to histone acetylation.

In recent years, epigenetic modifications have been increasingly regarded as an important hallmark of cancer. Histone acetylation, as an important part of epigenetic modification, plays a key role in the progress, treatment, and prognosis of many cancers. In this study, based on the TCGA database, we performed LASSO regression and the Cox algorithm to establish a prognostic signature of ovarian cancer associated with histone acetylation modulator genes and verified it externally in the GEO database. Subsequently, we performed an immunological bioinformatics analysis of the model from multiple perspectives using the CIBERSORT algorithm, ESTIMATE algorithm, and TIDE algorithm to verify the accuracy of the model. Based on the prognostic model, we divided ovarian cancer patients into high-risk and low-risk groups, and assessed survival and the efficacy of accepting immunosuppressive therapy. In addition, based on the analysis of characteristics of the model, we also screened targeted drugs for high-risk patients and predicted potential drugs that inhibit platinum resistance through the connectivity map method. We ultimately constructed a histone acetylation modulator-related signature containing 10 histone acetylation modulators, among which HDAC1, HDAC10, and KAT7 can act as independent prognostic factors for ovarian cancer and are related to poor prognosis. In the analysis of the tumor microenvironment, the proportion of the B-infiltrating cells and the macrophages was significantly different between the high- and low-risk groups. Also, the samples with high-risk scores had higher tumor purity and lower immune scores. In terms of treatment, patients in the high-risk group who received immunotherapy had a higher likelihood of immune escape or rejection and were less likely to respond to platinum/paclitaxel therapy. Finally, we screened 20 potential drugs that could target the model for reference.

Risk Assessment of Chlorothalonil as a Probable Human Carcinogen on Selected Vegetables in an Eastern China Province.

Objectives: This study aimed to provide an assessment of chlorothalonil's possible carcinogenic risk posed to the public. In combination and comparison with the non-carcinogenic risk, the results hopefully could provide useful insights, early warning, and references for policy formulation. Methods: This study firstly investigated the occurrence of chlorothalonil on selected key vegetables for different scenarios, and then conducted an exposure assessment with officially published data. Lastly, both the non-carcinogenic and carcinogenic risk of chlorothalonil were calculated by using Monte-Carlo simulation. Results: Even though mean non-carcinogenic risks of chlorothalonil for all scenarios were below threshold value, the mean carcinogenic risks for maximum-risk scenario and most-likely risk scenario were mostly above threshold value. High probabilities of exceedance of threshold value existed for carcinogenic risk under all scenarios. Conclusion: Potential threat to public health existed for conventionally 'safe' pesticide if considering the possible carcinogenicity. Extra caution should be taken and the potential carcinogenic effects should be included into consideration for better protection of public health during the policy formulation process.

Efficacy and safety of ixazomib maintenance therapy for patients with multiple myeloma: a meta-analysis.

OBJECTIVES: Multiple myeloma(MM) is a malignant plasma cell disease. Maintenance treatment is beneficial to prolong survival time in patients with MM. Ixazomib was approved for the treatment of relapsed or refractory MM in combination with lenalidomide and dexamethasone. Here, we carried out a meta-analysis to determine the efficacy and safety of ixazomib maintenance therapy. METHODS: Several databases were searched including PubMed, Web of Science, Embase, the Cochrane Library, etc. The last search dated back to July, 2020. Three clinical trials with a total of 1440 participants with newly diagnosed MM were included. RESULTS AND CONCLUSION: The pooled HR of progression-free survival (PFS) was 0.69 (95% CI = 0.59-0.79), which suggested ixazomib maintenance therapy could prolong PFS remarkably. In addition, ixazomib was effective in deepening remission (RR = 1.57, 95% CI = 1.26-1.96). But it could not significantly prolong PFS in cytogenetic high-risk patients (HR = 0.74, 95% CI = 0.47-1.00). In terms of adverse reactions, our analysis revealed higher incidences of grade 3-4 thrombocytopenia (RR = 7.47, 95% CI = 2.06-27.06), neuropathy (RR = 1.48, 95% CI = 1.14-1.92), grade 3-4 infections (RR = 1.77, 95% CI = 1.21-2.59) and gastrointestinal disorders (RR = 1.48, 95% CI = 1.32-1.66). There was no significant correlation between the use of ixazomib and grade 3-4 neutropenia (RR = 1.46, 95% CI = 0.77-2.78, p = 0.25) or the occurrence of new primary malignant tumor (RR = 0.88, 95% CI = 0.53-1.46, p = 0.62). Additionally, more RCTs are needed for better choice of treatment regimen.

Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury.

Human adipose-derived stem cells (hADSCs) are increasingly presumed to be a prospective stem cell source for cell replacement therapy in various degenerative and/or traumatic diseases. The potential of trans-differentiating hADSCs into motor neuron cells indisputably provides an alternative way for spinal cord injury (SCI) treatment. In the present study, a stepwise and efficient hADSC trans-differentiation protocol with retinoic acid (RA), sonic hedgehog (SHH), and neurotrophic factors were developed. With this protocol hADSCs could be converted into electrophysiologically active motoneuron-like cells (hADSC-MNs), which expressed both a cohort of pan neuronal markers and motor neuron specific markers. Moreover, after being primed for neuronal differentiation with RA/SHH, hADSCs were transplanted into SCI mouse model and they survived, migrated, and integrated into injured site and led to partial functional recovery of SCI mice. When ablating the transplanted hADSC-MNs harboring HSV-TK-mCherry overexpression system with antivirial Ganciclovir (GCV), functional relapse was detected by motor-evoked potential (MEP) and BMS assays, implying that transplanted hADSC-MNs participated in rebuilding the neural circuits, which was further confirmed by retrograde neuronal tracing system (WGA). GFP-labeled hADSC-MNs were subjected to whole-cell patch-clamp recording in acute spinal cord slice preparation and both action potentials and synaptic activities were recorded, which further confirmed that those pre-conditioned hADSCs indeed became functionally active neurons in vivo. As well, transplanted hADSC-MNs largely prevented the formation of injury-induced cavities and exerted obvious immune-suppression effect as revealed by preventing astrocyte reactivation and favoring the secretion of a spectrum of anti-inflammatory cytokines and chemokines. Our work suggests that hADSCs can be readily transformed into MNs in vitro, and stay viable in spinal cord of the SCI mouse and exert multi-therapeutic effects by rebuilding the broken circuitry and optimizing the microenvironment through immunosuppression.

Quantitative proteomic analysis revealed changes in protein synthesis and mitochondrial functions after acute DNA damage in mouse neural stem cells.

Considering the accumulation of DNA damages are frequently associated with neurodevelopmental disease, neurodegeneration, and brain tumors, exploration of the molecular mechanisms in mouse neural stem cells (NSCs) after DNA damage would be paramount useful for understanding the pathogenesis of these diseases. In present study, we utilized hydroxyurea (HU) treatment to cultured mouse NSCs to induce acute DNA damages. After HU treatment, mouse NSCs displayed elevated reactive oxygen species (ROS) level and compromised DNA repair in HR and NHEJ pathways. Furthermore, we performed quantitative proteomic analysis to unravel the protein variations. GO analysis and IPA suggested proteins participated in protein synthesis, mitochondrial metabolism and oxidative phosphorylation were under great changes after acute DNA damage. Overall, these data provide valuable insight into the molecular and biological changes in NSCs in the circumstance of acute DNA damage, and will help to discover the connections between DNA damage and potential diseases in brain.

Human adipose-derived stem cells partially rescue the stroke syndromes by promoting spatial learning and memory in mouse middle cerebral artery occlusion model.

INTRODUCTION: Growing evidence has brought stem cell therapy to the forefront as new promising approaches towards stroke treatment. Of all candidate seeding cells, adipose-derived stem cells (ADSCs) are considered as one of the most appropriate for stroke treatment. However, previous experimental data could not reach to an agreement on the efficacy of ADSC transplantation for treating stroke in vivo as well as its mechanism which hinders their further clinical translational application. METHODS: To explore their in vivo mechanism of hADSC administration on neurological injury, hADSC were labeled with Enhanced Green Fluorescence Protein expressing FG12 lentivirus and injected into MCAO mouse infarct area by in situ way. Neurological function was evaluated by Rogers Scaling System and their spatial learning and memory was determined by Morris Test. 2,3,5-triphenyltetrazolium chloride was carried out to compare the infarct area among groups. Histoimmunostaining was used to track the injected hADSCs for their in vivo migration, transdifferentiation and integration with the endogenous neuronal circuitry. To better address the underlying rescuing mechanism, qRT-PCR was performed on neural markers of MBP, MAP2, GFAP, microglia marker of Iba1. RESULTS: It was found that hADSCs could promote both spatial learning and memory of MCAO mice. Co-localization of GFP and MAP2 were found in the whole cortex with significantly (P<0.01) higher percentage at the contralateral cortex compared with the ipsilateral cortex. Low percentage of GFP and GFAP co-localized cells were found at whole cortex. Meanwhile, Iba1(+) microglia and GFAP(+) astrocyte cells were significantly (P<0.05) suppressed by hADSC injection. CONCLUSIONS: hADSCs could transdifferentiate into neuron like cells (MAP2(+)) in vivo and probably used as seeding cells for replacement based stem cell therapy of stroke. Also, significant immunomodulation was found. Meanwhile hADSCs could significantly protect the endogenous neuron survival. This study demonstrated that hADSC intervention with MCAO mice could apparently ameliorate stroke symptoms by direct cell replacement, enhanced immnunosuppression and increasing the viability of endogenous neurons.