Smart Nanoplatform for Visualizing Hydrogen Sulfide and Amplifying Oxidative Stress to Tumor Apoptosis.

Oxidative stress is involved in various signaling pathways and serves a key role in inducing cell apoptosis. Therefore, it is significant to monitor oxidative stress upon drug release for the assessment of therapeutic effects in cancer cells. Herein, a glutathione (GSH)-responsive surface-enhanced Raman scattering (SERS) nanoplatform is proposed for ultra-sensitively monitoring the substance related with oxidative stress (hydrogen sulfide, H2S), depleting reactive sulfur species and releasing anticancer drugs to amplify oxidative stress for tumor apoptosis. The Au@Raman reporter@Ag (Au@M@Ag) nanoparticles, where a 4-mercaptobenzonitrile molecule as a Raman reporter was embedded between layers of gold and silver to obtain sensitive SERS response, were coated with a covalent organic framework (COF) shell to form a core-shell structure (Au@M@Ag@COFs) as the SERS nanoplatform. The COF shell loading doxorubicin (DOX) of Au@M@Ag@COFs exhibited the GSH-responsive degradation capacity to release DOX, and its Ag layer as the sensing agent was oxidized to Ag2S by H2S to result in its prominent changes in SERS signals with a low detection limit of 0.33 nM. Moreover, the releasing DOX can inhibit the generation of H2S to promote the production of reactive oxygen species, and the depletion of reactive sulfur species (GSH and H2S) in cancer cells can further enhance the oxidative stress to induce tumor apoptosis. Overall, the SERS strategy could provide a powerful tool to monitor the dynamic changes of oxidative stress during therapeutic processes in a tumor microenvironment.

A multi-channel responsive AuNP@COF core-shell nanoprobe for simultaneous subcellular profiling of multiple cancer biomarkers.

The abnormal change in the expression profile of multiple cancer biomarkers is closely related to tumor progression and therapeutic effect. Due to their low abundance in living cells and the limitations of existing imaging techniques, simultaneous imaging of multiple cancer biomarkers has remained a significant challenge. Here, we proposed a multi-modal imaging strategy to detect the correlated expression of multiple cancer biomarkers, MUC1, microRNA-21 (miRNA-21) and reactive oxygen (ROS) in living cells, based on a porous covalent organic framework (COF) wrapped gold nanoparticles (AuNPs) core-shell nanoprobe. The nanoprobe is functionalized with Cy5-labeled MUC1 aptamer, a ROS-responsive molecule (2-MHQ), and a miRNA-21-response hairpin DNA tagged by FITC as the reporters for different biomarkers. The target-specific recognition can induce the orthogonal molecular change of these reporters, producing fluorescence and Raman signals for imaging the expression profiles of membrane MUC1 (red fluorescence channel), intracellular miRNA-21 (green fluorescence channel), and intracellular ROS (SERS channel). We further demonstrate the capability of the cooperative expression of these biomarkers, along with the activation of NF-κB pathway. Our research provides a robust platform for imaging multiple cancer biomarkers, with broad potential applications in cancer clinical diagnosis and drug discovery.

Dual-Modal Apoptosis Assay Enabling Dynamic Visualization of ATP and Reactive Oxygen Species in Living Cells.

ATP and reactive oxygen species (ROS) are considered significant indicators of cell apoptosis. However, visualizing the interplay between apoptosis-related ATP and ROS is challenging. Herein, we developed a metal-organic framework (MOF)-based nanoprobe for an apoptosis assay using duplex imaging of cellular ATP and ROS. The nanoprobe was fabricated through controlled encapsulation of gold nanorods with a thin zirconium-based MOF layer, followed by modification of the ROS-responsive molecules 2-mercaptohydroquinone and 6-carboxyfluorescein-labeled ATP aptamer. The nanoprobe enables ATP and ROS visualization via fluorescence and surface-enhanced Raman spectroscopy, respectively, avoiding the mutual interference that often occurs in single-mode methods. Moreover, the dual-modal assay effectively showed dynamic imaging of ATP and ROS in cancer cells treated with various drugs, revealing their apoptosis-related pathways and interactions that differ from those under normal conditions. This study provides a method for studying the relationship between energy metabolism and redox homeostasis in cell apoptosis processes.

Downregulation of DDIT4 ameliorates abnormal behaviors in autism by inhibiting ferroptosis via the PI3K/Akt pathway.

Autism spectrum disorder (ASD) is a complex disease with unclear etiology. Studies have shown that ferroptosis is also related to ASD progression, but the specific mechanism is still unclear. Valproic acid (VPA) induced neuronal ferroptosis in vitro. Mechanistic studies showed that both VPA and ferroptosis inducers promoted the expression of DDIT4 in neurons, thereby inhibiting the activation of the PI3K/Akt pathway. DDIT4 increased the accumulation of ROS, MDA and Fe2+, inhibited neuronal viability and downregulated GPX4 expression by inactivating the PI3K/Akt pathway. Ferroptosis inhibitors reversed the anti-survival effect of DDIT4, indicating that DDIT4 enhances ferroptosis through the PI3K/Akt pathway, thereby inhibiting neuronal viability. Further in vivo experiments found that autistic mice had high levels of ROS, MDA and Fe2+, increased DDIT4 expression, and downregulated expression levels of GPX4, p-PI3K and p-Akt; after downregulation of DDIT4 expression, the accumulation of ROS, MDA and Fe2+ was significantly reduced, while the expression levels of GPX4, p-PI3K and p-Akt were upregulated, indicating that DDIT4 knockdown reduces ferroptosis in autistic mice. In addition, DDIT4 downregulation, PI3K/Akt pathway activation, and ferroptosis inhibitors all improved social behavior deficits, repetitive stereotyped and compulsive behaviors, anxiety and exploratory behaviors in autistic mice, but PI3K/Akt pathway inhibitors significantly blocked the rescue of abnormal behaviors by DDIT4 downregulation in autistic mice. Therefore, downregulation of DDIT4 expression ameliorates abnormal behaviors in autism by inhibiting ferroptosis via the PI3K/Akt pathway, indicating that DDIT4, the PI3K/Akt pathway and ferroptosis have key roles in autism.

Acquired unilateral alopecia after arterial infusion chemotherapy in a recurrent nasopharyngeal carcinoma.

BACKGROUND: Intractable nasopharyngeal hemorrhage is a severe complication with high mortality rate in patients with radiation therapy (RT) for nasopharyngeal carcinoma (NPC) that requires emergency treatment. Quite a few of them combine with tumor recurrence. Treatment planning for these patients is extremely difficult for oncologists, and effective treatments are lacking. CASE: A 42-year-old man had a history of recurrent NPC that was treated with 2 cycles of chemoradiotherapies from 2017 to 2019. Five months after the second round of chemoradiotherapy, an episode of massive nasal bleeding occurred. As positron emission tomography (PET) scan revealed tumor recurrence in the left wall of nasopharynx, superselective embolization and subsequent intra-arterial infusion (IA, 4 times of cisplatin 60 mg + fluorouracil 1.0 g) were performed to stop bleeding and achieve tumor control. To date, the disease-free survival time has been over 1 year. No tumor recurrence or rebleeding is found except for alopecia on the left side. CONCLUSIONS: Interventional radiology is important and effective in the treatment of recurrent NPC for both massive nasal bleeding and tumor control. However, the unique complication of unilateral alopecia should not be ignored.

Comparing the 7th and 8th editions of UICC/AJCC staging system for nasopharyngeal carcinoma in the IMRT era.

BACKGROUND: To compare the prognostic value of 7th and 8th editions of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system for patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy and simultaneous integrated boost- intensity-modulated radiation therapy (SIB-IMRT). METHODS: Patients with NPC (n = 300) who received SIB-IMRT were included. Survival by T-classification, N-classification, and stage group of each staging system was assessed. RESULTS: For T-classification, nonsignificant difference was observed between T1 and T3 and between T2 and T3 disease (P = 0.066 and 0.106, respectively) for overall survival (OS) in the 7th staging system, whereas all these differences were significant in the 8th staging system (all P < 0.05). The survival curves for disease-free survival (DFS) and locoregional recurrence-free survival (LRRFS) in both staging systems were similar, except for the comparison of T2 and T4 disease for LRRFS (P = 0.070 for 7th edition; P = 0.011 for 8th edition). For N-classification, significant differences were observed between N2 and N3 diseases after revision (P = 0.046 and P = 0.043 for OS and DFS, respectively). For staging system, no significant difference was observed between IVA and IVB of 7th edition. CONCLUSION: The 8th AJCC staging system appeared to have superior prognosis value in the SIB-IMRT era compared with the 7th edition.

[Wolffian Adnexal Tumor:Report of One Case].

This article reports a patient who suffered from Wolffian adnexal tumor.We also briefly elucidate the pathogenesis,clinicopathological features,diagnosis,differentiation,and treatment of Wolffian adnexal tumor,with an attempt to increase the awareness of the disease and reduce misdiagnosis.

A phenylboronate-based SERS nanoprobe for detection and imaging of intracellular peroxynitrite.

A surface-enhanced Raman scattering (SERS) based nanoprobe was developed for detection and imaging of endogenous peroxynitrite in living cells. The probe was fabricated by assembling 3-mercaptophenylboronic acid pinacol ester onto the surface of gold nanoparticles (AuNPs). The detection of peroxynitrite is accomplished via measurement of the changes in the SERS spectra (at 882 cm-1) that are caused by the reaction between probe and peroxynitrite. The probe has a fast response (<30 s), a 0.4 µM lower detection limit and a wide linearity range from 5.0 × 10-7 to 1.0 × 10-4 M. It is biocompatible and highly stable on storage and under various pH conditions. Both the reaction and the SERS signal are highly specific over other species. The nanoprobe was successfully applied to SERS imaging of peroxynitrite that is produced in macrophages under oxidative stress. Conceivably, the method has a most viable tool for use in studies on peroxynitrite-related physiological and pathological processes. Graphical abstract Schematic presentation of surface-enhanced Raman scattering (SERS) nanoprobes fabricated by assembling phenylboronate on gold nanoparticles (AuNPs) for detecting intracellular peroxynitrite (ONOO-) via specific reaction-caused SERS changes.

[Expression of SLC25A38 in leukemic cells from children with acute lymphoblastic leukemia].

This study was aimed to investigate the SLC25A38 expression in pediatric patients with acute lymphoblastic leukemia (ALL) and its clinical significance. A total of 23 newly diagnosed ALL pedictric patients were enrolled in test group, 10 pediatric patients with non-hematologic malignancies were selected as control group. The expression in protein and mRNA levels of SLC25A38 were detected by Western blot and real-time PCR respectively. The results showed that the SLC25A38 protein was positive in 8 of 23 pediatric ALL patients (34.78%), while no positive case was found in 10 controls. The relative expression level of SLC25A38 mRNA was 0.4673 ± 0.05344 in SLC25A38-protein positive group of ALL patients, while that was 1.296 ± 0.2517 in SLC25A38-protein negative group of ALL patients. The expression level of SLC25A38 mRNA in SLC25A38-protein positive group was significantly lower than that in negative group (P = 0.001) . No statistically significant difference was found in comparison of SLC25A38-protein negative group of ALL patients with the control group (P = 0.1097). The analysis of clinical data showed that there were significantly differences in sex, immunophenotype, initial peripheral white blood cell count and LDH between the SLC25A38-protein positive and SLC25A38-protein negative groups (P < 0.05). It is concluded that as a novel protein, SLC25A38 highly expressed in pediatric ALL patients, indicating that SLC25A38 may serve as a molecular marker and potential therapeutic target for acute lymphoblastic leukemia in children.

[Molecular mechanism of Doxorubicin resistance in multiple myeloma cell line].

This study was aimed to investigate the molecular mechanism of doxorubicin resistance in multiple myeloma cell line and certify the effect of Notch signal over-expression on drug resistance of myeloma cells. The doxorubicin RPMI 8226 cell line (RPMI8226/DOX) was established by culturing 8226 cells with continuous low concentration and intermittent gradually-increasing-concentration of doxorubicin in vitro, the mRNA expression of Notch2,Jagged1, Jagged2, HES1 were measured by RT-PCR and the P-170 protein expression was detected by Western blot in RPMI 8226 cell line; the changes of IL-6 and VEGF were tested by ELISA. The results showed that the Notch mRNA expression (Notch2, Jagged1, Jagged2 increased gradually along with the increase of chemotherapeutic drug resistance, but the expression of HESI mRNA gradually decreased along with the increase of drug resistance. The expression level of P-170 protein was upregulated gradually along with the increase of drug resistance. The level of VEGF and IL-6 in culture supernatants of RPMI8226/DOX was higher than that in RPMI 8226. It is concluded that the establishment of RPMI 8226/DOX cell line is a useful model to analyze the mechanism of chemotherapeutic drug resistance in multiple myeloma, Notch activation is closely correlated with the drug resistance of multiple myeloma and Notch signaling may to be used as a new target for multiple myeloma treatment.

[Research on NPM1 gene mutations in acute myeloid leukemia].

Nucleolar phosphoprotein (nucleophosmin 1, NPM1), also known as B23, N038, is located in the nucleolar particles of a multifunctional protein widely expressed in various types of cells. At present, a number of studies found that the NPM1 gene mutation is the most frequent acquired molecular genetic abnormalities in acute myeloid leukemia (AML), especially in normal karyotype AML (nk-AML). NPM1 mutation is a special subgroup in AML, which has relatively unique clinical features, and is the independent prognostic indicators of AML. Research on NPM1 mutation has an important clinical significance in the diagnosis, treatment and prognosis judgment of AML patients. This article reviews the discovery of NPM1 gene mutation in AML in recent years, including structure and physiological functions of NPM1 gene, NPM1 gene mutation in AML, detection methods of NPM1 gene mutation, and so on.