The RAS-signaling-pathway-mutation-related prognosis in B-cell acute lymphoblastic leukemia: A report from South China children's leukemia group.

The next-generation sequencing technologies application discovers novel genetic alterations frequently in pediatric acute lymphoblastic leukemia (ALL). RAS signaling pathway mutations at the time of relapse ALL frequently appear as small subclones at the time of onset, which are considered as the drivers in ALL relapse. Whether subclones alterations in the RAS signaling pathway should be considered for risk group stratification of ALL treatment is not decided yet. In this work, we investigate the RAS signaling pathway mutation spectrum and the related prognosis in pediatric ALL. We employed an NGS panel comprising 220 genes. NGS results were collected from 202 pediatric ALL patients. 155 patients (76.7%) harbored at least one mutation. The incidences of RAS signaling pathway mutations are different significantly between T-ALL and B-ALL. In B-ALL, the RAS pathway is mostly involved, and NRAS (17.6%), KRAS (22.7%), and PTPN11 (7.7%) were the three most frequently mutated genes. Co-occurring mutations of CREBBP and NRAS, FLT3, or PTPN11 (p = 0.002, p = 0.009, and p = 0.003, respectively) were found in this cohort. The 3-year RFS rates for the RAS signaling pathway mutation-positive and negative cases was 76.5 % versus 89.7 % (p = 0.012). Four cases relapsed in the lately 3 years were RAS signaling pathway mutation-positive. RAS signaling pathway mutation is an important biomarker for poorer relapse-free survival in pediatric B-ALL patients despite good early MRD levels.

Integration of single-cell RNA-seq and bulk RNA-seq to construct liver hepatocellular carcinoma stem cell signatures to explore their impact on patient prognosis and treatment.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a prevalent form of primary liver cancer. Research has demonstrated the contribution of tumor stem cells in facilitating tumor recurrence, metastasis, and treatment resistance. Despite this, there remains a lack of established cancer stem cells (CSCs)-associated genes signatures for effectively predicting the prognosis and guiding the treatment strategies for patients diagnosed with LIHC. METHODS: The single-cell RNA sequencing (scRNA-seq) and bulk RNA transcriptome data were obtained based on public datasets and computerized firstly using CytoTRACE package and One Class Linear Regression (OCLR) algorithm to evaluate stemness level, respectively. Then, we explored the association of stemness indicators (CytoTRACE score and stemness index, mRNAsi) with survival outcomes and clinical characteristics by combining clinical information and survival analyses. Subsequently, weighted co-expression network analysis (WGCNA) and Cox were applied to assess mRNAsi-related genes in bulk LIHC data and construct a prognostic model for LIHC patients. Single-sample gene-set enrichment analysis (ssGSEA), Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) analysis were employed for immune infiltration assessment. Finally, the potential immunotherapeutic response was predicted by the Tumor Immune Dysfunction and Exclusion (TIDE), and the tumor mutation burden (TMB). Additionally, pRRophetic package was applied to evaluate the sensitivity of high and low-risk groups to common chemotherapeutic drugs. RESULTS: A total of four genes (including STIP1, H2AFZ, BRIX1, and TUBB) associated with stemness score (CytoTRACE score and mRNAsi) were identified and constructed a risk model that could predict prognosis in LIHC patients. It was observed that high stemness cells occurred predominantly in the late stages of LIHC and that poor overall survival in LIHC patients was also associated with high mRNAsi scores. In addition, pathway analysis confirmed the biological uniqueness of the two risk groups. Personalized treatment predictions suggest that patients with a low risk benefited more from immunotherapy, while those with a high risk group may be conducive to chemotherapeutic drugs. CONCLUSION: The current study developed a novel prognostic risk signature with genes related to CSCs, which provides novel ideas for the diagnosis, prognosis and treatment of LIHC.

Case report: Robust response to sintilimab in advanced distal cholangiocarcinoma with PD-L1 expression and DNA damage repair.

Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient's liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.

miRNA-383-5p Regulated Migration and Invasion of Tumor Cells by Inhibiting NCKAP1 Expression in Gastric Cancer.

Gastric cancer (GC) is the second deadliest disease in Asia, so it is crucial to find its promising therapeutic targets. The expression profile data of miR383-5p in the Cancer Genome Atlas (TCGA) were analyzed. The expression levels of miR383-5p in the collected clinical tissue samples and peripheral blood samples were examined by qPCR, and the relationship between its expression and the clinical data of patients was evaluated. MiR383-5p was overexpressed in the AGS cells, and cell biology assays, such as Transwell, were performed to detect the cell proliferation, migration, invasion and other cell biology abilities of miR383-5p. Target prediction and dual luciferase reporter gene assay were performed to find and validate the target genes of miR383-5p. The expression and activity of MMP and related proteins after overexpression of miR383-5p and NCKAP1 were detected by WB and gelatin zymography assay. The expression of miR383-5p was down-regulated in GC tissues, and its low expression was associated with lymph node metastasis. Restoration of miR383-5p expression in GC cells can inhibit the invasion and migration abilities of GC cells. MiR383-5p negatively regulated NCKAP1 through direct interaction with the 3'UTR sequence of NCKAP1. The overexpression of NCKAP1 can improve the migration and invasion abilities of GC cells, whereas overexpression of miR383-5p can inhibit growth of the aforementioned abilities of GC cells induced by NCKAP1 overexpression. The overexpression of NCKAP1 can increase the expression level and activity of MMP2, while the overexpression of miR383-5p can inhibit the increase of MMP2 expression level and activity in GC cells induced by NCKAP1 overexpression. NCKAP1 is a target gene of miR383-5p, and miR383-5p could be a valuable therapeutic target for stomach adenocarcinoma.

Knowledge, attitude, and practice toward leukemia in the general population and among family members of patients with leukemia: A cross-sectional study.

Background: Patients with leukemia rely on social and family support. This study aimed to explore the knowledge, attitude, and practice (KAP) toward leukemia among family members of patients with leukemia and the general population in southeast China. Methods: A cross-sectional study was conducted in September 2022 in southeast China (Anhui Province). The KAP scores and demographic data were assessed by questionnaire and analyzed by multivariable logistic regression and structural equation modeling. Results: A total of 760 valid questionnaires were collected, including 117 (15.39%) answered by family members of patients with leukemia. The mean knowledge (8.30 ± 2.79 vs. 8.72 ± 2.56, P = 0.103), attitude (52.17 ± 5.52 vs. 52.27 ± 5.53, P = 0.862), and practice (8.06 ± 2.00 vs. 8.18 ± 2.05, P = 0.547) scores were comparable among family members and the general population. Higher knowledge scores [OR = 1.18 (1.10, 1.27), P < 0.001] and higher attitude scores [OR = 1.05 (1.02, 1.09), P = 0.002] were independently associated with better practice scores. Being a family member of a patient with leukemia had no significant effect on the KAP scores. Conclusion: The participants demonstrated satisfactory knowledge, positive attitude, and appropriate practices toward leukemia, suggesting that access to information about leukemia to the general public might be sufficient in China. Health education might effectively improve knowledge, which could translate into improved attitude and practice.

Autophagy-driven regulation of cisplatin response in human cancers: Exploring molecular and cell death dynamics.

Despite the challenges posed by drug resistance and side effects, chemotherapy remains a pivotal strategy in cancer treatment. A key issue in this context is macroautophagy (commonly known as autophagy), a dysregulated cell death mechanism often observed during chemotherapy. Autophagy plays a cytoprotective role by maintaining cellular homeostasis and recycling organelles, and emerging evidence points to its significant role in promoting cancer progression. Cisplatin, a DNA-intercalating agent known for inducing cell death and cell cycle arrest, often encounters resistance in chemotherapy treatments. Recent studies have shown that autophagy can contribute to cisplatin resistance or insensitivity in tumor cells through various mechanisms. This resistance can be mediated by protective autophagy, which suppresses apoptosis. Additionally, autophagy-related changes in tumor cell metastasis, particularly the induction of Epithelial-Mesenchymal Transition (EMT), can also lead to cisplatin resistance. Nevertheless, pharmacological strategies targeting the regulation of autophagy and apoptosis offer promising avenues to enhance cisplatin sensitivity in cancer therapy. Notably, numerous non-coding RNAs have been identified as regulators of autophagy in the context of cisplatin chemotherapy. Thus, therapeutic targeting of autophagy or its associated pathways holds potential for restoring cisplatin sensitivity, highlighting an important direction for future clinical research.

Central venous pressure combined with renal venous impedance index in predicting the acute kidney injury after thoracic and abdominal (non-cardiac) surgery.

BACKGROUND: In the 21st century, 13% of patients undergoing open abdominal surgery, 25% of patients undergoing heart surgery, and 57% of patients admitted to the intensive care unit (ICU) are affected by acute kidney injury (AKI). METHODS: This prospective observational study included patients admitted directly to the ICU between June 2021 and December 2021. RESULTS: A total of 81 patients were enrolled after thoracic and abdominal (non-cardiac) surgery; 36 patients (44.4%) were diagnosed with AKI occurred within 7 days after surgery. Six-hour postoperative central venous pressure(CVP) was a risk factor for AKI in thoracic and abdominal (non-cardiac) postoperative patients (odds ratio [OR], 1.418; 95% confidence intervals [CI], 1.106-1.819; P = 0.006). Six-hour postoperative vein impedance index(VII) and CVP were significantly positively correlated (P = 0.031). The combination of 6-h postoperative VII with CVP (VII ≥0.34, CVP ≥7.5 mmHg) showed an area under the curve (AUC) of 0.787, In the subgroup analysis of patients with 6-h postoperative CVP <7.5 mmHg, there was a significant statistical difference in 6-h postoperative VII between the groups and those without AKI (P = 0.048). At 6-h postoperative CVP <7.5 mmHg, VII of ≥0.44 had a predictive value for AKI after thoracic and abdominal (non-cardiac) surgery, with an AUC of 0.669, a sensitivity of 41.2%, and a specificity of 94.4%. CONCLUSION: Six-hour postoperative CVP combined with VII can better predict the occurrence of AKI occurred within 7 days after thoracic and abdominal (non-cardiac) surgery but cannot predict the severity of AKI.

Theory and experiment: The synthesis and drug application of "ON-OFF-ON" fluorescent probes for copper and biothiols detection.

Abnormal copper ions (Cu2+) and biothiols have potential impacts on environmental pollution and human health, so the detection of these substances with high selectivity and sensitivity has become an important research topic. In this study, we designed and synthesized two fluorescent probes (L1 and L2) based on naphthalene and anthracene derivatives that could specifically detect Cu2+ and biothiols. Owing to the paramagnetic effect of Cu2+, the strong fluorescent intensity was quenched after the addition of Cu2+. When biothiols were added to the solution (L-Cu2+), the fluorescence intensity was significantly enhanced and recovered. So, the interaction process was accompanied with "ON-OFF-ON" phenomenon in fluorescent intensity. Two complexes (L-Cu2+) showed low limit of detection for biothiols (Cys was 3.4 ×10-5 M and GSH was 2.0 ×10-5 M) and weak cytotoxicity (< 150 µg/mL). Theoretical investigation analysis revealed that the intramolecular hydrogen bond existed in the structure of probes and the roles of molecular frontier orbitals in molecular interplay. In addition, two probes also showed good applicability in actual drug Atomolan. The GSH content in the tested Atomolan reached over 99.9% of the labeling which was accord with the percentage of pharmacopoeia. Therefore, two probes have the real application value in the detection of Cu2+, biothiols and drug efficacy in various environments.

Adult localized Langerhans cell histiocytosis: A case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disease of Langerhans cells with unknown pathogenesis. An increasing number of clinicians recognize that LCH has a wide clinical spectrum and a highly varied course. Adults rarely develop LCH. Here, we report a case of adult localized LCH. CASE SUMMARY: A 32-year-old woman presented with plaques and ulcers on the vulva and crissum, accompanied by pain that persisted for more than one year. Physical examination revealed a red-infiltrating plaque with ulcerations and exudates in the vulva and crissum. Pathological examination revealed a diffuse infiltration of lymphocytes, eosinophilic granulocytes, and histiocytoid cells in the superficial dermis. Proliferative histiocytoid cells showed mild atypia, partly with kidney-shaped nuclei. Immunohistochemical examination showed that the histiocytoid cells were positive for S100 protein and CD1 and weakly positive for CD68 (20% +), with a Ki-67 index of 30%. Laboratory tests did not reveal any other systemic damage. The patient was diagnosed with adult localized LCH and was prescribed oral prednisone (20 mg) once daily. The skin lesions gradually improved and are still being followed-up. CONCLUSION: Adult localized LCH is rare and must be differentiated from other common conditions.

HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma.

Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.

The influence of methotrexate-related transporter and metabolizing enzyme gene polymorphisms on peri-engraftment syndrome and graft-versus-host disease after haplo-hematopoietic stem cell transplantation in pediatric patients with malignant hematological diseases.

Background: Methotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported. Methods: Here, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center. Results: We discovered all gene polymorphisms were in the Hardy-Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II-IV aGvHD (HR = 2.604, p = 0.039). Conclusion: In summary, our findings prove that the host's genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis.

Difunctional Fluorescent Probes for Iron and Hydrogen Sulfide Detection Based on Diphenyl Derivative.

In order to better monitor the content of Fe3+ and H2S in the biological environment, two new fluorescent probes were designed and synthesized. With the addition of Fe3+, the strong fluorescence emission of two probes was significantly quenched due to the paramagnetic effect of Fe3+. With the further addition of S2-, the fluorescence intensity was quickly restored. Two probes showed high selectivity and strong sensitivity for the detection of Fe3+ and S2-, and the fluorescence intensity "ON-OFF-ON" was accompanied with the interaction process. At the same time, two probes displayed good anti-interference ability which was not interfered by the existence of other ions. In addition, two probes illustrated fast response time to Fe3+, S2- and small cytotoxicity to cells. Therefore, two probes can provide a potential ideal tool for detecting Fe3+ and H2S in organisms and the environment.

Design, Synthesis, and Bioactivity of Aldisine Derivatives Containing Oxime and Hydrazine Moieties Based on Hydrogen Bonds.

Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel mode of action. Using antiviral alkaloid aldisine as the lead compound and drawing on the hydrogen bond effect widely used in drug design, derivatives containing oxime and hydrazone moieties were designed and synthesized by introducing functional groups with hydrogen-bond receptors or donors into molecules. The configuration of derivatives was systematically studied through nuclear Overhauser effect (NOE) spectroscopy and single crystal analysis. The antiviral activity test result showed that most derivatives had antiviral activity against tobacco mosaic virus (TMV), and some compounds had better activity than the commercial antiviral drug ribavirin, especially compounds 2 and 24, which had comparable activity to the most effective commercial antiviral drug ningnanmycin. Preliminary mode of action studies showed that compound 2 could affect the assembly of rod-shaped TMVs by promoting the aggregation and fragmentation of TMV coat proteins. Molecular docking experiments demonstrated that the introduction of oxime and hydrazone moieties could indeed increase the hydrogen bond between molecules and target proteins. In addition, we conducted fungicidal and larvicidal activities study of these derivatives. Most of these derivatives had good larvicidal activities against Mythimna separata and Plutella xylostella and showed broad-spectrum fungicidal activities.

Enriching Reaction Intermediates in Multishell Structured Copper Catalysts for Boosted Propanol Electrosynthesis from Carbon Monoxide.

Fine-tuned catalysts that alter the diffusion kinetics of reaction intermediates is of great importance for achieving high-performance multicarbon (C2+) product generation in carbon monoxide (CO) reduction. Herein, we conduct a structural design based on Cu2O nanoparticles and present an effective strategy for enhancing propanol electrosynthesis from CO. The electrochemical characterization, operando Raman monitoring, and finite-element method simulations reveal that the multishell structured catalyst can realize the enrichment of C1 and C2 intermediates by nanoconfinement space, leading to the possibility of further coupling. Consequently, the multishell copper catalyst realizes a high Faraday efficiency of 22.22 ± 0.38% toward propanol at the current density of 50 mA cm-2.

New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

The clinical impact of IKZF1 mutation in acute myeloid leukemia.

Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.