Au nano-cone array for SERS detection of associated miRNA in lymphoma patients.

Based on Au nano-cone array (Au-NCA) and a three-segment hybridization strategy, a novel SERS biosensor is proposed for the ultrasensitive detection of the microRNA miR-21. The uniform, stable, and reproducible Au-NCA was prepared by the single-layer colloidal ball template method. Subsequently, the target was hybridized with sequence 2. The resulting target-sequence 2 complex was then hybridized with sequence 1 anchored on Au-NCA. Thus, a three-segment sequence complex was formed. SERS measurements can be performed without the need for complex purification and amplification steps. Due to the ability of miR-21 to perform specific complementary hybridization with two sequences, SERS biosensors have superior specificity for miR-21 without interference from other miRNAs. Under the optimal conditions, the SERS biosensor was applied and the limit of detection (LOD) was as low as 3.02 aM. This method has been successfully used to the detection of miR-21 in the serum of lymphoma patients and healthy volunteers. The results are consistent with the traditional test methods. Therefore, this novel SERS biosensor shows excellent clinical translational potential in the detection of lymphoma.

Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of hepatocellular carcinoma (HCC).

Hepatocellular carcinoma (HCC) holds a prominent position among global cancer types. Classically, HCC manifests in individuals with a genetic predisposition when they encounter risk elements, particularly in the context of liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs), which are transcription factors activated by fatty acids, belong to the nuclear hormone receptor superfamily and play a pivotal role in the regulation of energy homeostasis. At present, three distinct subtypes of PPARs have been recognized: PPARα, PPARγ, and PPARß/δ. They regulate the transcription of genes responsible for cellular development, energy metabolism, inflammation, and differentiation. In recent years, with the rising incidence of HCC, there has been an increasing focus on the mechanisms and roles of PPARs in HCC. PPARα primarily mediates the occurrence and development of HCC by regulating glucose and lipid metabolism, inflammatory responses, and oxidative stress. PPARß/δ is closely related to the self-renewal ability of liver cancer stem cells (LCSCs) and the formation of the tumor microenvironment. PPARγ not only influences tumor growth by regulating the glucose and lipid metabolism of HCC, but its agonists also have significant clinical significance for the treatment of HCC. Therefore, this review offers an exhaustive examination of the role of the three PPAR subtypes in HCC progression, focusing on their mediation of critical cellular processes such as glucose and lipid metabolism, inflammation, oxidative stress, and other pivotal signaling pathways. At the end of the review, we discuss the merits and drawbacks of existing PPAR-targeted therapeutic strategies and suggest a few alternative combinatorial therapeutic approaches that diverge from conventional methods.

[The In Vivo Intervention and Relative Mechanism of Genistein on the Inflammation and Thrombophilia in Lymphoma-Bearing Mice].

OBJECTIVE: To investigate the in vivo intervention and relative mechanism of Genistein (GEN) on tumor-associated inflammatory and tumor thrombophilia in lymphoma-bearing mice. METHODS: Forty female Balb/c mice aged 5-6 weeks were injected with murine-derived Pro B-cell lymphoma cell line 38B9 to establish a lymphoma mouse model, which was randomly divided into control group, tumor-bearing group, GEN drug intervention group and cyclophosphamide (CTX）drug intervention group. Histopathologic was used to evaluate the tumorigenesis. Tumor formation was observed, and tumor tissues were collected of HE and immunohistochemical staining. ELISA and flow cytometry were used to detect the expression of inflammatory factors and the changes of thrombus indices in plasma after intervention of GEN and Cyclophosphamide (CTX) respectively. Immunohistochemistry method was used to detect the expression of CD19 in tomor tissues of tummor bearing mice. RESULTS: After 14 days of tumor bearing, the mice were tumorigenic. The lymphoma cells were diffusely distributed in the tumor tissue and the expression of CD19 in the tumor tissue was positive. The inflammatory factors such as IL-6, NETs and CLEC-2, and thrombotic indices such as TF, FIB and D-D in lymphoma-bearing mice were significantly higher than those before tumor-injection and lower than those after drug-intervention (all P<0.05). The levels of CLEC-2 and D-D in GEN group were significantly lower than those in CTX group (P<0.05). CONCLUSION: Tumor-associated inflammation and thrombophilia exist in lymphoma-bearing mice. GEN shows better anti-inflammatory and anti-thrombotic effects compared with CTX by interfering with tumor inflammatory factors.

Molecular Dynamics Simulations of the Mechanical Properties of Cellulose Nanocrystals-Graphene Layered Nanocomposites.

Cellulose nanocrystals (CNCs) have received a significant amount of attention due to their excellent physiochemical properties. Herein, based on bioinspired layered materials with excellent mechanical properties, a CNCs-graphene layered structure with covalent linkages (C-C bond) is constructed. The mechanical properties are systematically studied by molecular dynamics (MD) simulations in terms of the effects of temperature, strain rate and the covalent bond content. Compared to pristine CNCs, the mechanical performance of the CNCs-graphene layered structure has significantly improved. The elastic modulus of the layered structure decreases with the increase of temperature and increases with the increase of strain rate and covalent bond coverage. The results show that the covalent bonding and van der Waals force interactions at the interfaces play an important role in the interfacial adhesion and load transfer capacity of composite materials. These findings can be useful in further modeling of other graphene-based polymers at the atomic scale, which will be critical for their potential applications as functional materials.

Plasmonic Bi promotes the construction of Z-scheme heterojunction for efficient oxygen molecule activation.

Reactive oxygen species (ROS) are essential to photocatalytic degradation of antibiotics in water. In this work, we prepared Ag3PO4/Bi@Bi4Ti3O12 by simple in-situ reduction method and precipitation method, which improves the ability to capture visible light and increases the activity of photoinduced molecular oxygen activation, resulting in reactive oxygen species (ROS) such as superoxide radicals (•O2-), hydroxyl radicals (•OH), and H2O2. The excellent TC degradation efficiency derive from the SPR effect of the metal Bi on the surface enhances the light absorption intensity, and development of a Z-scheme heterojunction between Ag3PO4 and Bi4Ti3O12 promotes the activation of molecular oxygen. A possible photodegradation mechanism of the as-prepared photocatalyst was proposed. This work provides an insight perspective to the synthesis photocatalysts with molecular oxygen activation for environmental remediation.

Changes of Cytokines in Children With Tic Disorder.

Tic disorder (TD) is a common childhood-onset disease associated with abnormal development of brain networks involved in the motor and sensory processing. The underlying pathophysiological mechanisms in TD are still unclear. An involvement of immune mechanisms in its pathophysiology has been proposed. This study investigates the association between the changes of cytokines and the etiology and development of TD. Different expressions of cytokines in a larger number of samples in our study may provide new insights to the field. The levels of cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were evaluated in 1,724 patients who were clinically diagnosed with TD from 1 to 17.5 years old and 550 were from 6 months to 14.5 years old in the control group. We assessed the levels of cytokines according to the patient's medication status and the severity of the disease. Of the cytokines we investigated, the serum IL-6 concentration of children with TD was significantly higher than that of the control group, while the levels of other cytokines were lower in TD patients. In the patient group whose YTGSS score ranged from 1 to 9, the IL-4, IL-10, and IFN-γ levels increased in medication group compared to unmedication group. Our data suggested that the cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) may play an important role in the etiology and the severity in TD. Whether drug intervention in the early stage of tic disorder has a better effect on children needs further research.

TRPM2 ion channel is involved in the aggravation of cognitive impairment and down regulation of epilepsy threshold in pentylenetetrazole-induced kindling mice.

Epilepsy is one of the most common neurological conditions. Recent findings suggest that one of the mechanisms promoting its existence is calcium influx. The transient receptor potential melastatin type 2 channel (TRPM2) is a Ca2+-permeable cation channel that contributes to cell apoptosis; its possible signaling pathway is the PARP1/BNIP3/AIF/Endo G pathway that may be related to epilepsy. The aim of this study was to investigate the TRPM2 channel's involvement in epilepsy and how it works. We also explored the possible role of the TRPM2 channel on cognitive ability and emotion in epilepsy. To accomplish our goals, we used different animal epilepsy models to study the effect of the TRPM2 channel on epilepsy. The results showed that the knockout (KO) of the TRPM2 gene might play a protective role in epilepsy. Considering the advantages attributed to pentylenetetrazole (PTZ)-induced kindling mouse model, we used the model for the following assessments: 1. to observe changes in cognition and anxiety between wild type (WT) mice and TRPM2-KO mice with the recognition of new things trial and elevated plus-maze; 2. to determine the expression of apoptosis-associated proteins (PARP1, BNIP3, AIF, and Endo G) using Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot; 3. to observe neurons pathologic damages and astrocyte activation in each group. The main findings of our study were: (a) TRPM2-KO had a protective effect on epilepsy; (b) TRPM2-KO improved spatial memory deficits overtime during epilepsy, but it did not improve anxiety; (c) the protective effect probably occurred via the PARP1 downstream signaling pathway; (d) TRPM2-KO could ameliorate epilepsy-induced hippocampal pathological damages and weaken astrocyte activation. These findings may provide a new approach for the treatment of epilepsy and early intervention.

Erratum to efficacy and safety of mecapegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer: a randomized, multicenter, active-controlled phase III trial.

[This corrects the article DOI: 10.21037/atm.2019.07.95.].

Efficacy and safety of mecapegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer: a randomized, multicenter, active-controlled phase III trial.

BACKGROUND: Neutropenia is a common complication from chemotherapy. Mecapegfilgramtim (code name HHPG-19K), a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), has been developed. This study was to evaluate the efficacy and safety of mecapegfilgrastim for reducing neutropenia compared with filgrastim. METHODS: This was a randomized, controlled non-inferiority study. A total of 339 breast cancer patients who were eligible for (neo) adjuvant chemotherapy were randomized assigned into three groups to receive mecapegfilgrastim 100 µg/kg, mecapegfilgrastim fixed dose of 6 mg or filgrastim 5 µg/kg/day in the first cycle of chemotherapy. The primary endpoint was the duration of grade ≥3 neutropenia in cycle 1. The secondary endpoints included the duration of grade ≥3 neutropenia in cycles 2-4, incidence of grade ≥3 neutropenia, and febrile neutropenia (FN). The safety profile was also evaluated. RESULTS: The mean duration of grade ≥3 neutropenia was 1.06 [95% confidence interval (CI): 0.65, 1.26] days in mecapegfilgrastim 100 µg/kg group, 1.23 (95% CI: 0.84, 1.88) days in mecapegfilgrastim 6 mg group, and 2.06 (95% CI: 1.66, 2.46) days in the filgrastim group. The mean difference between mecapegfilgrastim 100 µg/kg and filgrastim was -1.00 (95% CI: -1.52, -0.48), the mean difference between mecapegfilgrastim 6 mg and filgrastim was -0.83 (95% CI: -1.36, -0.30). The upper bounds of 95% CI for the difference between mecapegfilgrastim and filgrastim were all <1 day (the predefined non-inferiority margin). For the incidence of grade ≥3 and grade 4 neutropenia, the mean duration of grade 4 neutropenia, mecapegfilgrastim showed better performance compared with filgrastim. For the incidence of FN, there was no difference between patients treated with mecapegfilgrastim and filgrastim. For safety profile, mecapegfilgrastim of two doses groups were all well-tolerated. Fixed 6 mg dose of mecapegfilgrastim exhibited comparable efficacy and safety in comparison with 100 µg/kg during 4 cycles. CONCLUSIONS: Long-acting mecapegfilgrastim (100 µg/kg and fixed 6 mg) is very effective and well tolerated when administered in the primary prophylaxis of chemotherapy induced neutropenia and in consecutive-cycle treatment. In some clinical parameters, mecafilgrastim is non-inferior and even superior to filgrastim. The fixed 6 mg-dose regimen showed similar efficacy and safety profile compared with 100 µg/kg regimen, and would be the preference in clinical practice, due to the convenient once-per-cycle administration and high-degree treatment compliance for the patients. This study provided new evidence for the novel long-acting rhG-CSF, mecapegfilgrastim, which would be a new alternative for clinical practice for prophylaxis of chemotherapy induced neutropenia.

A randomized multicenter phase II trial of mecapegfilgrastim single administration versus granulocyte colony-stimulating growth factor on treating chemotherapy-induced neutropenia in breast cancer patients.

BACKGROUND: This study aimed to evaluate the efficacy and safety of mecapegfilgrastim (HHPG-19K) with different doses compared to granulocyte colony-stimulating growth factor (G-CSF) in treating chemotherapy-induced neutropenia in breast cancer patients. METHODS: A total of 182 breast cancer patients were enrolled in this multi-center, randomized, phase II trial and developed neutropenia after first cycle chemotherapy. Patients were then assigned as 1:1:1 ratio to receive 100 µg/kg HHPG-19K single injection (HHPG-19K-N group), 150 µg/kg HHPG-19Ksingle injection (HHPG-19K-H group) and 5 µg/kg G-CSF daily injection (G-CSF group) at day 3 of the second cycle (cycle 2) chemotherapy. The primary endpoint was incidence of grade ≥3 neutropenia during cycle 2. Study drug-related adverse events during cycle 2 were recorded for safety assessment. RESULTS: During cycle 2 chemotherapy, both HHPG-19K-N and HHPG-19K-H groups exhibited lower incidence of grade ≥3 neutropenia compared with G-CSF group, while no difference was observed between HHPG-19K-N and HHPG-19K-H groups. Also, better outcomes were observed in HHPG-19K-N and HHPG-19K-H groups compared with G-CSF group regarding to grade 4 neutropenia, duration of grade ≥3 neutropenia, duration of grade 4 neutropenia, incidence of febrile neutropenia (FN) and rescue application of G-CSF, time to ANC recovery, while no difference of these outcomes between HHPG-19K-N and HHPG-19K-H groups was observed. For safety analysis, the incidences of hematologic and non-hematologic adverse events were similar among the 3 groups. CONCLUSIONS: HHPG-19K presents with better clinical efficacy as well as equal tolerance compared with G-CSF in treating chemotherapy-induced neutropenia in breast cancer patients.

[Association between familial febrile convulsions and HCN2 gene].

OBJECTIVE: To investigate the possible association of familial febrile convulsions with HCN2 gene. METHODS: PCR was conducted on the DNA of peripheral blood white cells from 60 children with familial febrile convulsion (FC) of Han nationality population in northern China aged 1.5 +/- 1.0 (8 months to 5 years old), to amplify the exons of HCN2 gene. The PCR products underwent sequencing to identify the possible mutations. 101 normal children from the same area were used as controls. RESULTS: No mutation was found in the exons of HCN2 gene, however, 14 single nucleotide polymorphisms (SNPs) were found among which there were 8 newly identified SNPs. Using 9 SNPs as markers, association study was conducted between the FC group and control group. There were no significant differences in allele frequencies and genotype frequencies of the 9 SNPs between the FC group and control group. CONCLUSION: HCN2 may not be a susceptibility gene for FC in Chinese population.