[Clinical Study of Venetoclax Combined with Azacitidine in the Treatment of Patients with Adult Acute Myeloid Leukemia].

OBJECTIVE: To evaluate the efficacy and side effects of venetoclax combined with azacitidine chemotherapy in the treatment of previously untreated adult patients with acute myeloid leukemia(AML). METHODS: A retrospective analysis was performed on 48 untreated adult AML patients admitted to the Department of Hematology, Affiliated Hospital of Jinggangshan University from January 2020 to December 2022. Among them, 26 patients received venetoclax combined with azacitidine chemotherapy (observation group), and 22 patients received daunorubicin plus cytarabine chemotherapy (control group). The differences in complete response (CR) rate, objective response rate (ORR), progressionfree survival (PFS), overall survival(OS) and adverse reactions (AR) were compared between the two groups. RESULTS: There was no significant difference in age, sex ratio, absolute value of trilineage cell and proportion of bone marrow primordial cells between the two groups before treatment (all P >0.05). The CR rate and the ORR rate of the observation group was significantly higher than that of the control group (P < 0.05). After treatment, there were no significant difference in the adverse reactions such as myelosuppression, granulocytosis, secondary infection, mucosal damage, liver and kidney damage, cardiotoxicity and gastrointestinal toxicity between the two groups (P >0.05). The median PFS and the median OS of the observation group were significantly better than those of the control group (P < 0.05). CONCLUSION: The remission rate of venetoclax combined with azacitidine was higher than that of conventional chemotherapy in previously untreated adult acute myeloid leukemia. Venetoclax combined with azacitidine chemotherapy could reduce hematologic related side reactions and prolong the remission period and survival of AML patients.

Clear Cell Renal Cell Carcinoma: Characterizing the Phenotype of Von Hippel-Lindau Mutation Using MRI.

BACKGROUND: The von Hippel-Lindau (VHL) mutation is an important alteration in clear cell renal cell carcinoma (ccRCC); however, its imaging phenotype remains unclear. PURPOSE: To investigate whether MRI features can reflect the VHL mutation status. STUDY TYPE: Retrospective. FIELD STRENGTH/SEQUENCE: 3 T/fast spin echo T2-weighted, spin-echo echo planar diffusion-weighted, gradient recalled echo T1-weighted, gradient recalled echo chemical-shift T1-weighted, and contrast-enhanced gradient recalled echo T1-weighted sequences. POPULATION: One hundred five patients with ccRCC who underwent preoperative contrast-enhanced MRI and subsequent genomic sequencing: 59 consecutive patients from our institution (38 [64.41%] with VHL mutations) formed a training cohort, and 46 from The Cancer Genome Atlas (TCGA) database (24 [52.17%] with VHL mutations) formed an independent test cohort. ASSESSMENT: Two radiologists, with 23 and 33 years of experience respectively, jointly evaluated the semantic MRI features of the primary lesion in ccRCCs to propose potential features related to VHL mutations in both cohorts. Three additional readers, with 5, 7, and 10 years of experience respectively, independently reviewed all lesions to assess the interobserver agreement of MRI features. A VHL mutational likelihood score (VHL-MULIS) system was constructed using the training cohort and validated using the independent test cohort. STATISTICAL TESTS: Fisher's test or chi-square test, t-test or Mann-Whitney U test, logistic regression, Cohen's kappa (κ), area under the receiver operating characteristic curve (AUC). A two-sided P value <0.05 was considered statistically significant. RESULTS: In both the local and public cohorts, T2-weighted signal intensity and presence of microscopic fat from primary lesions were significantly associated with VHL mutation status. The VHL-MULIS incorporated maximum diameter, T2-weighted signal intensity, and presence of microscopic fat in the training cohort and demonstrated promising diagnostic ability (AUC, 0.82; sensitivity, 0.79; specificity, 0.82) and substantial interobserver agreement (κ, 0.787) in the test cohort. DATA CONCLUSION: The VHL mutation exhibited a distinct MRI phenotype. Integrating multiple semantic MRI features has potential to reflect the mutation status in patients with ccRCC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Correction: Li et al. TRIM10 Is Downregulated in Acute Myeloid Leukemia and Plays a Tumor Suppressive Role via Regulating NF-κB Pathway. Cancers 2023, 15, 417.

In the original publication [...].

Immunotherapy-relevance of a candidate prognostic score for Acute Myeloid Leukemia.

Background: Acute Myeloid Leukemia (AML) exhibits a wide array of phenotypic manifestations, progression patterns, and heterogeneous responses to immunotherapies, suggesting involvement of complex immunobiological mechanisms. This investigation aimed to develop an integrated prognostic model for AML by incorporating cancer driver genes, along with clinical and phenotypic characteristics of the disease, and to assess its implications for immunotherapy responsiveness. Methods: Critical oncogenic driver genes linked to survival were identified by screening primary effector and corresponding gene pairs using data from The Cancer Genome Atlas (TCGA), through univariate Cox proportional hazard regression analysis. This was independently verified using dataset GSE37642. Primary effector genes were further refined using LASSO regression. Transcriptomic profiling was quantified using multivariate Cox regression, and the derived prognostic score was subsequently validated. Finally, a multivariate Cox regression model was developed, incorporating the transcriptomic score along with clinical parameters such as age, gender, and French-American-British (FAB) classification subtype. The 'Accurate Prediction Model of AML Overall Survival Score' (APMAO) was developed and subsequently validated. Investigations were conducted into functional pathway enrichment, alterations in the gene mutational landscape, and the extent of immune cell infiltration associated with varying APMAO scores. To further investigate the potential of APMAO scores as a predictive biomarker for responsiveness to cancer immunotherapy, we conducted a series of analyses. These included examining the expression profiles of genes related to immune checkpoints, the interferon-gamma signaling pathway, and m6A regulation. Additionally, we explored the relationship between these gene expression patterns and the Tumor Immune Dysfunction and Exclusion (TIDE) dysfunction scores. Results: Through the screening of 95 cancer genes associated with survival and 313 interacting gene pairs, seven genes (ACSL6, MAP3K1, CHIC2, HIP1, PTPN6, TFEB, and DAXX) were identified, leading to the derivation of a transcriptional score. Age and the transcriptional score were significant predictors in Cox regression analysis and were integral to the development of the final APMAO model, which exhibited an AUC greater than 0.75 and was successfully validated. Notable differences were observed in the distribution of the transcriptional score, age, cytogenetic risk categories, and French-American-British (FAB) classification between high and low APMAO groups. Samples with high APMAO scores demonstrated significantly higher mutation rates and pathway enrichments in NFKB, TNF, JAK-STAT, and NOTCH signaling. Additionally, variations in immune cell infiltration and immune checkpoint expression, activation of the interferon-γ pathway, and expression of m6A regulators were noted, including a negative correlation between CD160, m6A expression, and APMAO scores. Conclusion: The combined APMAO score integrating transcriptional and clinical parameters demonstrated robust prognostic performance in predicting AML survival outcomes. It was linked to unique phenotypic characteristics, distinctive immune and mutational profiles, and patterns of expression for markers related to immunotherapy sensitivity. These observations suggest the potential for facilitating precision immunotherapy and advocate for its exploration in upcoming clinical trials.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.

Flexible Ureteroscopy with a Tip-Flexible Pressure-Controlling Ureteral Access Sheath for Renal Stones in Children.

INTRODUCTION: The aim of this study was to evaluate the safety and efficacy of flexible ureteroscopy using a tip-flexible pressure-controlling ureteral access sheath (TFPC-UAS) for renal stones in children. METHODS: Consecutive patients aged 5-18 years with renal stones of diameter 1-3 cm were enrolled between January 2022 and November 2023 at Ganzhou People's Hospital. The patients were treated with flexible ureteroscopy using the TFPC-UAS. The renal pelvic pressure (RPP) parameters were set as follows: control value at -10 mm Hg to 5 mm Hg, warning value at 20 mm Hg, and limit value at 30 mm Hg. The infusion flow rate was set to 100-120 mL/min. A holmium laser (276 µm) was used to fragment the stone at 2.0-2.5 J/pulse with a frequency of 20-30 pulses/s. The cases were analyzed for RPP, operative time, stone-free rate, and complications. RESULTS: A total of 21 consecutive patients were included. Two patients were switched to percutaneous nephrolithotomy owing to sheath placement failure. The RPP was -4.6 ± 2.1 mm Hg. The mean operative time was 56.5 ± 17.1 min. The postoperative hospitalization time was 1.5 ± 0.3 days. The stone-free rates at 1 day and 1 month after surgery were 81.0% and 85.7%, respectively. Residual stones in 2 patients were cleared after extracorporeal shockwave lithotripsy. Three cases of Clavien I complications and one case of Clavien II complications occurred. No major complications (Clavien grade III-V) were observed. CONCLUSIONS: Flexible ureteroscopy with a TFPC-UAS is safe and effective for renal stones in children.

Fluid absorption during flexible ureteroscopy with intelligent control of renal pelvic pressure: a randomized controlled trial.

PURPOSE: To investigate fluid absorption and its influencing factors during flexible ureteroscopy with intelligent control of renal pelvic pressure (RPP). METHODS: A total of 80 patients with upper urinary tract calculi underwent flexible ureteroscopy with intelligent control of RPP by pressure-measuring ureteral access sheath and were randomly divided into four groups. The RPP of Groups A, B, and C were set at - 5, 0 and 5 mmHg, respectively. Conventional flexible ureteroscopy with uncontrolled pressure served as control Group D. The perfusion flow rate was set at 100 ml/min in the four groups, with 20 patients in each group. The fluid absorption was measured by 1% ethanol every 10 min. Operation time, stone-free rate, and complications were recorded. RESULT: Seventy-three patients were finally included in the RCT. The general and preoperative data of the patients were comparable between the groups. The fluid absorption of Groups A, B, and C was significantly less than that of Group D (P < 0.01). Fluid absorption and operation time were positively correlated, and the correlation coefficients R were 0.864, 0.896, 0.918, and 0.947, respectively (P < 0.01). The fluid absorption of patients with vomiting, fever and ureteral injury was greater than that of patients without complications in the four groups (P < 0.01). In different groups, fluid absorption was greater in patients with ureteral injury Post-Ureteroscopic Lesion Scale (PULS) 1-3 than in noninjured patients (P < 0.01). CONCLUSION: Flexible ureteroscopy with intelligent control of RPP effectively reduces the absorption of perfusion fluid. Operation time and ureteral injury are also key factors affecting perfusion fluid absorption. REGISTRATION NUMBER AND DATE: NCT05201599; August 11, 2021.

T cell-mediated tumor killing sensitivity gene signature-based prognostic score for acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: Acute myeloid leukemia (AML) is an aggressive, heterogenous hematopoetic malignancies with poor long-term prognosis. T-cell mediated tumor killing plays a key role in tumor immunity. Here, we explored the prognostic performance and functional significance of a T-cell mediated tumor killing sensitivity gene (GSTTK)-based prognostic score (TTKPI). METHODS: Publicly available transcriptomic data for AML were obtained from TCGA and NCBI-GEO. GSTTK were identified from the TISIDB database. Signature GSTTK for AML were identified by differential expression analysis, COX proportional hazards and LASSO regression analysis and a comprehensive TTKPI score was constructed. Prognostic performance of the TTKPI was examined using Kaplan-Meier survival analysis, Receiver operating curves, and nomogram analysis. Association of TTKPI with clinical phenotypes, tumor immune cell infiltration patterns, checkpoint expression patterns were analysed. Drug docking was used to identify important candidate drugs based on the TTKPI-component genes. RESULTS: From 401 differentially expressed GSTTK in AML, 24 genes were identified as signature genes and used to construct the TTKPI score. High-TTKPI risk score predicted worse survival and good prognostic accuracy with AUC values ranging from 75 to 96%. Higher TTKPI scores were associated with older age and cancer stage, which showed improved prognostic performance when combined with TTKPI. High TTKPI was associated with lower naïve CD4 T cell and follicular helper T cell infiltrates and higher M2 macrophages/monocyte infiltration. Distinct patterns of immune checkpoint expression corresponded with TTKPI score groups. Three agents; DB11791 (Capmatinib), DB12886 (GSK-1521498) and DB14773 (Lifirafenib) were identified as candidates for AML. CONCLUSION: A T-cell mediated killing sensitivity gene-based prognostic score TTKPI showed good accuracy in predicting survival in AML. TTKPI corresponded to functional and immunological features of the tumor microenvironment including checkpoint expression patterns and should be investigated for precision medicine approaches.

The effect and safety assessment of monitoring ethanol concentration in exhaled breath combined with intelligent control of renal pelvic pressure on the absorption of perfusion fluid during flexible ureteroscopic lithotripsy.

PURPOSE: Previously, we designed a ureteral access sheath with the capability of renal pelvic pressure (RPP) measurement and a medical perfusion and aspiration platform, allowing for the intelligent control of RPP. However, the effect of different RPP levels on perfusion fluid absorption remains unclear. This randomized controlled trial aimed to investigate the effects of exhaled ethanol concentration monitoring and intelligent pressure control on perfusion fluid absorption during flexible ureteroscopic lithotripsy. METHODS: Eighty patients scheduled for flexible ureteroscopic lithotripsy were randomly divided into four groups. In groups A, B, and C, the RPPs were set at 0, - 5, and - 10 mmHg, respectively. Group D was regarded as the controls with unfixed RPP. Isotonic saline containing 1% ethanol was used as the irrigation fluid, with an average irrigation flow rate of 100 mL/min. The primary outcome of this study was the absorption of perfusion fluid that was calculated based on the exhaled ethanol concentration. The secondary outcomes included duration of operation and amounts of perfusion fluid used. Postoperative complications, pre- and postoperative renal function, infection markers, and blood gas analysis were also recorded for safety assessment. RESULTS: In all, 76 patients were involved in this study, whose demographic characteristics and preoperative conditions were comparable among groups. Under the same perfusion flow rate, the groups with fixed RPP exhibited reduced absorption of perfusion fluid, duration of operation, and perfusion volume. In particular, the lowest values were observed in group C (RPP = - 10 mmHg). In contrast to the unfixed RPP group, no considerable difference were observed in levels of BUN, Scr, WBC, CRP, and blood gas values among the fixed RPP groups. Moreover, postoperative complications showed no significant difference among groups. CONCLUSION: In flexible ureteroscopic lithotripsy, the groups with fixed RPP had less absorption of perfusion fluid and perfusion volume, shorter duration of surgery, and higher safety than the unfixed group.

A Serum-Stable supramolecular drug carrier for chemotherapeutics fabricated by a Peptide-Photosensitizer conjugate.

Supramolecular assemblies fabricated by peptide-photosensitizer conjugates have attracted increasing attentions in recent years as drug carriers for chemotherapeutics (CTs). However, these assemblies have been known to suffer from disintegration by serum components leading to off-target drug release, and thereby impairing antitumor effects and causing systemic toxicities. To address this problem, this study reports a nano-architectural self-assembly peptide-photosensitizer carrier (NSPC) fabricated by conjugating a phthalocyanine derivative (MCPZnPc) and ε-poly-l-lysine (EPL). By engineering the core and peripheral interactions, MCPZnPC-EPL (M-E) NSPC firmly encapsulated multiple CTs, creating CT@M-E NSPCs that were highly stable against disintegration in serum. More importantly, CT@M-E NSPCs exhibited controlled release of CTs in tumor tissues. The antitumor effects of CTs were further promoted by the synergism with the reactivated photodynamic effect. Furthermore, M-E NSPC-encapsulation optimized CTs' biodistribution reducing adverse effects in vivo. This study provides a serum-stable supramolecular drug delivery system with photodynamic effect, which is applicable for a broad-range of CTs to promote antitumor effects and ameliorate adverse effects.

[Research Progress of Next Generation Sequencing in Acute Leukemia --Review].

With the advent of precision medicine, next-generation sequencing (NGS) is playing an increasingly important role in clinical oncology diagnosis and treatment with its advantages of high sensitivity, high accuracy, high efficiency and operability. NGS reveals the genetic characteristics of acute leukemia(AL) patients by screening for specific disease-causing genes to identify occult as well as complex genetic mutations in patients with AL, leading to early diagnosis and targeted drug therapy for AL patients, as well as to predict disease recurrence by detecting mnimal residual disease (MRD) and analyzing mutated genes to determine patient prognosis. NGS plays an increasingly important role in the diagnosis, treatment and prognosis assessment in AL, providing a direction for the pursuit of precision medicine. This paper reviews the research progress of NGS in AL.

Physicians' knowledge of invasive fungal disease in China.

BACKGROUND: Invasive fungal disease (IFD) is associated with high morbidity and mortality. Data are lacking regarding physicians' perspectives on the diagnosis and management of IFD in China. OBJECTIVES: To evaluate physicians' perspectives on the diagnosis and management of IFD. METHODS: Based on current guidelines, a questionnaire was designed and administered to 294 physicians working in haematology departments, intensive care units, respiratory departments and infectious diseases departments in 18 hospitals in China. RESULTS: The total score and subsection scores for invasive candidiasis, invasive aspergillosis (IA), cryptococcosis and invasive mucormycosis (IM) were 72.0 ± 12.2 (maximum = 100), 11.1 ± 2.7 (maximum = 19), 43.0 ± 7.8 (maximum = 57), 8.1 ± 2.0 (maximum = 11) and 9.8 ± 2.3 (maximum = 13), respectively. Although the perspectives of the Chinese physicians were in good overall agreement with guideline recommendations, some knowledge gaps were identified. Specific areas in which the physicians' perspectives and guideline recommendations differed included use of the ß-D-glucan test to facilitate the diagnosis of IFD, relative utility of the serum galactomannan test and bronchoalveolar lavage fluid galactomannan test in patients with agranulocytosis, use of imaging in the diagnosis of mucormycosis, risk factors for mucormycosis, indications for initiating antifungal therapy in patients with haematological malignancies, when to start empirical therapy in mechanically ventilated patients, first-line drugs for mucormycosis and treatment courses for IA and IM. CONCLUSION: This study highlights the main areas that could be targeted by training programs to improve the knowledge of physicians treating patients with IFD in China.

Analgesic Efficacy of an Ultrasound-Guided Transversus Thoracis Plane Block Combined with an Intermediate Cervical Plexus Block on Postoperative Pain Relief After Trans-Areolar Endoscopic Thyroidectomy: A Single Center Prospective Randomized Controlled Study.

Purpose: This study aimed to investigate the analgesic effect of ultrasound-guided transversus thoracis plane block (TTPB) combined with intermediate cervical plexus block (ICPB) in the early postoperative period after trans-areolar endoscopic thyroidectomy. Patients and Methods: A total of 62 female patients undergoing trans-areolar endoscopic thyroidectomy were randomly classified to the TTPB combined with ICPB group with ropivacaine (block group) or superficial cervical plexus block group (control group). The primary outcome measures were resting visual analogue scale (VAS) in the chest area at 6 h after surgery. The secondary outcome measures included chest resting and movement VAS score, neck resting and movement VAS score within 24 h after surgery, intraoperative remifentanil consumption, postoperative analgesia rate and analgesic requirements and patient satisfaction score for pain management at discharge. Results: Compared with the control group, the block group at rest showed consistently lower VAS scores in the chest area at 6 and 12 h after operation; the block group at rest showed lower VAS scores in the neck at 6, 12 and 24 h after operation. Regarding movement, the VAS scores of the chest and neck area at 2, 6, 12 and 24 h after the operation were lower in the block group than in the control group. The consumption of remifentanil, rate of postoperative analgesic requirements, and consumption of postoperative rescue analgesia in the block group were lower than those in the control group. Satisfaction with pain treatment at discharge was higher in the block group than in the control group. Conclusion: Ultrasound-guided TTPB combined with ICPB provides good analgesic effect in the early postoperative period after trans-areola endoscopic thyroidectomy.

TRIM10 Is Downregulated in Acute Myeloid Leukemia and Plays a Tumor Suppressive Role via Regulating NF-κB Pathway.

BACKGROUND: Accumulating evidence suggests that members of the tripartite motif (TRIMs) family play a crucial role in the development and progression of hematological malignancy. Here, we explored the expression and potential role of TRIM10 in acute myeloid leukemia (AML). METHODS: The expression levels of TRIM10 were investigated in AML patients and cell lines by RNA-seq, qRT-PCR and Western blotting analysis. Lentiviral infection was used to regulate the level of TRIM10 in AML cells. The effects of TRIM10 on apoptosis, drug sensitivity and proliferation of AML cells were evaluated by flow cytometry and cell-counting kit-8 (CCK-8) assay, as well as being assessed in a murine model. RESULTS: TRIM10 mRNA and protein expression was reduced in primary AML samples and AML cell lines in comparison to the normal controls and a human normal hematopoietic cell line, respectively. Moreover, overexpression of TRIM10 in HL60 and K562 cells inhibited AML cell proliferation and induced cell apoptosis. The nude mice study further confirmed that overexpression of TRIM10 blocked tumor growth and inhibited cell proliferation. In contrast, knockdown of TRIM10 in AML cells showed contrary results. Subsequent mechanistic studies demonstrated that knockdown of TRIM10 enhanced the expression of nuclear protein P65, which implied the activation of the NF-κB signal pathway. Consistently, overexpression of TRIM10 in AML cells showed a contrary result. These data indicated that inactivation of the NF-κB pathway is involved in TRIM10-mediated regulation in AML. TRIM10 expression can be de-repressed by a combination that targets both DNA methyltransferase and histone deacetylase. CONCLUSIONS: Our results strongly suggested that TRIM10 plays a tumor suppressive role in AML development associated with the NF-κB signal pathway and may be a potential target of epigenetic therapy against leukemia.

Prediction of Potential Biomarkers in Early-Stage Nasopharyngeal Carcinoma Based on Platelet RNA Sequencing.

Early diagnosis is essential for the treatment and prevention of nasopharyngeal cancer. However, there is a lack of effective biological indicators for nasopharyngeal carcinoma (NPC). Therefore, we explored the potential biomarkers in tumour-educated blood platelet (TEP) RNA in early NPC. Platelets were isolated from blood plasma and their RNA was extracted. High-throughput sequenced data from a total of 33 plasma samples were analysed using DESeq2 to identify the differentially expressed genes (DEGs). Subsequently, the DEGs were subjected to principal component analysis (PCA), gene ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; and Cytoscape, TargetScan, and miRanda software were used for inferring the competing endogenous RNA network. We identified 19 long non-coding (lnc) RNAs (DElncRNAs) and 248 mRNAs (DEmRNAs) that were differentially expressed in the TEP RNA. In addition, SELP gene mRNA and lncRNAs AC092135.3, AC012358.2, AL021807.1, AP001972.5, and GPX1 were found to be down-regulated DEmRNA and DElncRNAs in the early stage of NPC. Bioinformatic analysis showed that these DEmRNAs and DElncRNAs may be involved in regulating the pathogenesis of NPC. Our research may provide new insights for exploring the biological mechanisms of NPC and early diagnosis using potential biomarkers.

Biochar and organic fertilizer drive the bacterial community to improve the productivity and quality of Sophora tonkinensis in cadmium-contaminated soil.

Excessive Cd accumulation in soil reduces the production of numerous plants, such as Sophora tonkinensis Gagnep., which is an important and widely cultivated medicinal plant whose roots and rhizomes are used in traditional Chinese medicine. Applying a mixture of biochar and organic fertilizers improved the overall health of the Cd-contaminated soil and increased the yield and quality of Sophora. However, the underlying mechanism between this mixed fertilization and the improvement of the yield and quality of Sophora remains uncovered. This study investigated the effect of biochar and organic fertilizer application (BO, biochar to organic fertilizer ratio of 1:2) on the growth of Sophora cultivated in Cd-contaminated soil. BO significantly reduced the total Cd content (TCd) in the Sophora rhizosphere soil and increased the soil water content, overall soil nutrient levels, and enzyme activities in the soil. Additionally, the α diversity of the soil bacterial community had been significantly improved after BO treatment. Soil pH, total Cd content, total carbon content, and dissolved organic carbon were the main reasons for the fluctuation of the bacterial dominant species. Further investigation demonstrated that the abundance of variable microorganisms, including Acidobacteria, Proteobacteria, Bacteroidetes, Firmicutes, Chloroflexi, Gemmatimonadetes, Patescibacteria, Armatimonadetes, Subgroups_ 6, Bacillus and Bacillus_ Acidiceler, was also significantly changed in Cd-contaminated soil. All these alterations could contribute to the reduction of the Cd content and, thus, the increase of the biomass and the content of the main secondary metabolites (matrine and oxymatrine) in Sophora. Our research demonstrated that the co-application of biochar and organic fertilizer has the potential to enhance soil health and increase the productivity and quality of plants by regulating the microorganisms in Cd-contaminated soil.

Orai1-mediated store-operated Ca2+ entry promotes cervical cancer progression through IL-6 signaling.

Cervical cancer is a major cause of cancer-associated mortality among women in developing countries. Orai1-mediated store-operated Ca2+ entry (SOCE) is the primary mechanism underlying most of the non-excitable calcium influx into cells. There is at present limited evidence showing that Orai1 can function as an oncogene or a tumor suppressor depending on the cancer type. Furthermore, the exact biological functions of Orai1 in cervical cancer and the underlying mechanisms are still poorly understood. In this study, we found that Orai1 was upregulated in cervical cancer tissues, and promoted the growth of human cervical cancer cells both in vitro and in vivo. Gene silencing of Orai1 in cervical cancer cells significantly decreased interleukin (IL)-6 secretion. Interestingly, exogenous IL-6 abrogated the effects of Orai1 silencing and restored the clonogenicity of cervical cancer cells. Furthermore, we also observed a positive correlation between Orai1 and IL-6 expression in human cervical cancer samples. Taken together, our findings indicate that Orai1 functions as an oncogene in cervical cancer and is a promising therapeutic target.

Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway.

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice.

Evaluating the effect of anti-nausea drugs in IDO enzyme gene expression and preventing postoperative vomiting and nausea in patients undergoing general anesthesia: A Meta-analysis.

Nausea and vomiting are known as side effects after surgery. Since serotonin antagonist drugs are widely used to prevent nausea and vomiting after surgery, the present study was conducted to compare the effectiveness of this group's drugs, namely, ondansetron and palonosetron. On the other hand, recent studies have shown that the metabolites of the kynurenine pathway in the Suppression of the immune response play a role. Indoleamine 2,3 dioxygenase (IDO) is the main enzyme controlling this pathway. Therefore, the effect of these two drugs on IDO gene expression was evaluated. The present study is a systematic review with meta-analysis. The search was conducted in the Cochrane, PubMed, Clinical K, and CRD databases for randomized clinical trial articles that compared two drugs, palonosetron, and ondansetron, regarding nausea and vomiting in patients undergoing surgery with general anesthesia. In the end, eight studies were included in the meta-analysis. STATA13 statistical software was used to estimate the overall risk, relative risk, and data analysis. The results showed that the number of samples in all articles was 739. The analysis of the results between 0 and 24 hours showed that palonosetron reduces the incidence of nausea by 50% and the incidence of vomiting by 79% compared to ondansetron (p=0.001). Also, there was no difference between the IDO gene expression in the two drug groups (p>0.05). In general, the analysis of the results related to the effectiveness of palonosetron and ondansetron 24 hours after surgery with a dose of 0.075 mg of palonosetron versus 4 mg of ondansetron showed that palonosetron is more effective in reducing the incidence of nausea and vomiting in patients than ondansetron.