IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT.

The heterogeneous molecular subtypes of gliomas demonstrate varied responses to chemotherapy and distinct prognostic outcomes. Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation are associated with better outcomes and are more responsive to temozolomide (TMZ) compared to those without IDH1 mutation. IDH1-mutant gliomas elevate D-2-hydroxyglutarate (D-2HG) levels, with potential dual effects on tumor progression. Limited research has explored the potential anti-glioma effects of D-2HG in combination with TMZ. Clinical data from over 2500 glioma patients in our study confirms that those with IDH1 mutations exhibit enhanced responsiveness to TMZ chemotherapy and a significantly better prognosis compared to IDH1 wild-type patients. In subsequent cellular experiments, we found that the IDH1-mutant metabolite D-2HG suppresses Integrin subunit beta 4 (ITGB4) expression, and down-regulate the phosphorylation levels of PI3K and AKT, ultimately inhibiting cell proliferation while promoting apoptosis, thereby improving glioma prognosis. Additionally, we have demonstrated the synergistic effect of D-2HG and TMZ in anti-glioma therapy involved inhibiting the proliferation of glioma cells and promoting apoptosis. Finally, by integrating data from the CGGA and TCGA databases, it was validated that ITGB4 expression was lower in IDH1-mutant gliomas, and patients with lower ITGB4 expression were associated with better prognosis. These findings indicate that ITGB4 may be a promising therapeutic target for gliomas and D-2HG inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT. These findings drive theoretical innovation and research progress in glioma therapy.

Multi-dimensional cylindrical vector beam (de)multiplexing through cascaded wavelength- and polarization-sensitive metasurfaces.

Cylindrical vector beams (CVBs) exhibit great potential for multiplexing communication, owing to their mode orthogonality and compatibility with conventional wavelength multiplexing techniques. However, the practical application of CVB multiplexing communication faces challenges due to the lack of effective spatial polarization manipulation technologies for (de)multiplexing multi-dimensional physical dimensions of CVBs. Herein, we introduce a wavelength- and polarization-sensitive cascaded phase modulation strategy that utilizes multiple coaxial metasurfaces for multi-dimensional modulation of CVBs. By leveraging the spin-dependent phase modulation mechanism, these metasurfaces enable the independent transformation of the two orthogonal polarization components of CVB modes. Combined with the wavelength sensitivity of Fresnel diffraction in progressive phase modulation, this approach establishes a high-dimensional mapping relationship among CVB modes, wavelengths, spatial positions, and Gaussian fundamental modes, thereby facilitating multi-dimensional (de)multiplexing involving CVB modes and wavelengths. As a proof of concept, we theoretically demonstrate a 9-channel multi-dimensional multiplexing system, successfully achieving joint (de)multiplexing of 3 CVB modes (1, 2, and 3) and 3 wavelengths (1550 nm, 1560 nm, and 1570 nm) with a diffraction efficiency exceeding 80%. Additionally, we show the transmission of 16-QAM signals across 9 channels with the bit-error-rates below 10-5. By combining the integrability of metasurfaces with the high-dimensional wavefront manipulation capabilities of multilevel modulation, our strategy can effectively address the diverse demands of different wavelengths and CVB modes in optical communication.

Differences in brain activation during working memory tasks between badminton athletes and non-athletes: An fNIRS study.

BACKGROUND: Working memory refers to our ability to temporarily store and process information, and it is crucial for efficient cognition and motor control. In the context of badminton matches, athletes need to make quick decisions and reactions in rapidly changing situations. Athletes with strong working memory capacity can better process this information and translate it into actual motor performance. Although previous research has demonstrated that exercise can improve brain function and structure, it remains unclear how the brain functions of athletes engaged in long-term professional training are specifically involved in performing working memory tasks. METHOD: In this study, we assessed behavioral performance and cerebral oxygenation in the prefrontal lobe, using functional near-infrared spectroscopy, with 22 athletes and 30 non-athletes. Each participant was evaluated while performing 1-back, 2-back, and 3-back tasks. The area under the curve (AUC) of HbO (oxyhemoglobin) is used as an indicator of cortical brain oxygenation. RESULTS: The behavioral performance results indicated no difference between badminton athletes and non-athletes in the n-back task. We observed significantly different activation in channels of left FPA, right DLPFC, and left VLPFC when performing 3-back tasks. Brain activation indicated that long-term training in badminton caused a better performance in high-load working memory tasks. CONCLUSIONS: Long-term professional training in badminton primarily activates the left frontal-parietal attention network (left FPA), right dorsolateral prefrontal cortex (right DLPFC), and left ventrolateral prefrontal cortex (left VLPFC) during working memory tasks.

Comprehensive pharmacogenomics characterization of temozolomide response in gliomas.

Recent developments in pharmacogenomics have created opportunities for predicting temozolomide response in gliomas. Temozolomide is the main first-line alkylating chemotherapeutic drug together with radiotherapy as standard treatments of high-risk gliomas after surgery. However, there are great individual differences in temozolomide response. Besides the heterogeneity of gliomas, pharmacogenomics relevant genetic polymorphisms can not only affect pharmacokinetics of temozolomide but also change anti-tumor effects of temozolomide. This review will summarize pharmacogenomic studies of temozolomide in gliomas which can lay the foundation to personalized chemotherapy.

Maternal yeast-based nucleotide supplementation decreased stillbirth by regulating nutrient metabolism.

BACKGROUND: As an enzymatic product of yeast, yeast-based nucleotide (YN) is rich in nucleotides. To test the effects of maternal dietary supplementation with YN during late pregnancy on placental nutrient transport and nutrient metabolism in neonatal piglets, 64 pregnant sows (day 85 ± 3) were assigned into two groups: (i) control (CON) and (ii) treatment (YN; 4 g kg-1 ). Blood, placenta and liver samples of neonates during delivery were collected. RESULTS: The results showed that maternal YN supplementation decreased stillbirth rate and intra-uterine growth restriction rate (P < 0.05). In addition, maternal YN supplementation increased total serum protein, albumin and total cholesterol (P < 0.05). Furthermore, in neonatal piglets in the YN group, both serum amino acidand nucleotide profiles were affected, as well as liver amino acid, and fatty acid profiles were regulated (P < 0.05). Moreover, maternal YN supplementation increased liver mRNA expression of SLC28A3, SLC29A1, SLC29A2, PC, PCK1, FBP1, SREBP1c, HSL and CYP7a1 of neonatal piglets (P < 0.05). Meanwhile, there was a decrease in placental gene expression of EAAT2, EAAT3, LAT1 and PAT1, as well as lower protein expression of peroxisome proliferator-activated receptor (PPAR)γ, AKT, phosphorylated-AKT, phosphorylated-mammalian target of rapamycin (mTOR) and Raptor, in the YN group (P < 0.05). CONCLUSION: Taken together, these results indicate that maternal YN supplementation regulates placental nutrient transport by regulating the mTOR complex 1-PPAR pathway, and affects the liver metabolism of nucleotides, amino acids and fatty acids in neonatal piglets, thereby improving the reproductive performance of sow to a certain extent. © 2020 Society of Chemical Industry.

[Study on the sorption behavior of tetracycline onto activated sludge].

The batch sorption methods were employed to investigate the sorption behavior of tetracycline (TC) on the activated sludge. It was shown that the mixed liquor suspended solids (MLSS) and the initial concentration of TC had great impacts on equilibrium time, adsorption capacity and adsorption rate. Compared with pseudo first-order model, pseudo second-order model showed the better agreement. At 10, 25 degrees C, the Langmuir model was the best isotherm to describe the experimental data for adsorption of TC on activated sludge, and the maximum adsorption capacities were 31.14, 70.95 mg x g(-1) respectively; at 40 degrees C, the linear isotherm confirmed the agreement. The data were also modeled by D-R isotherm to determine the type of adsorption. At 10 degrees C (E was 9.13 kJ x mol(-1)), the dominant type was physical, and at 40 degrees C (E was 7.07 kJ x mol(-1)), the dominant type was chemical. With the temperature increasing, the adsorption capacity increased. Ion exchange is one mechanism for adsorption of TC on activated sludge. When the initial concentrations of TC were 5, 10, 20 mg x L(-1), with the Na+ concentration increasing from 0 mol x L(-1) to 0.1 mol x L(-1), the adsorption capacities decreased by 15.32%, 15.00%, 20.12% respectively. The maximum adsorption capacity was got at pH 6 when pH varied from 5 to 10.

[The value of von Willebrand factor pro-peptide and ADAMTS13 in diagnosis of thrombotic thrombocytopenic purpura].

OBJECTIVE: To evaluate the combined analysis of ADAMTS13 activity and von Willebrand factor (vWF) pro-peptide level in the diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP). METHODS: ADAMTS13 activity was measured by Fluorescenced substrate method (with Frets-vWF73), and vWF pro-peptide was measured by sandwich ELISA in 11 patients with idiopathic TTP, 5 patients with secondary TTP, 2 patients with transplantation associated TTP and 3 patients with suspected TTP. Plot each patient's data in the graph with coordinates of ADAMTS13/vWF pro-peptide. The plot was divided into 4 quadrants by 2 lines, one went through 10% in ADMATS13 axis, and the other went through 3 in vWF pro-peptide axis. Analyze the characteristics of points in different quadrants. RESULTS: Mean ADAMTS13 activities of idiopathic, secondary, transplantation associated and suspected TTP were 6.90%, 3.88%, 13.2% and 19.46% respectively. Mean times of elevated vWF pro-peptide from normal plasma pool of idiopathic, secondary, transplantation associated and suspected TTP were 4.2, 3.2, 4.5 and 2.9 respectively. In ADAMTS13/vWF pro-peptide figure, 57.1% of patients with TTP were in quadrant III, IV, all patients with transplantation associated TTP were in quadrant II ,2 of 3 patients with suspected TTP were in quadrant I. CONCLUSION: Combined analysis of ADAMTS13 and vWF pro-peptide may provide clues and advices in the diagnosis and treatment of TTP, especially for the suspected ones.

Development and identification of monoclonal antibodies against parathion.

An amino-derivative of parathion was prepared and conjugated to human serum albumin (HSA) and bovine thyroglobulin (BTG) via diazonium condensation. Spleen cells producing high titer antibody were removed and fused with myeloma cells of SP2/0 origin. Using a conventional immunization protocol, we generated nine stable murine monoclonal antibodies (MAbs) producing cell lines to parathion. After four successive limiting dilutions, antibodies produced by nine clones had high affinities, ranging from 10(9) to 10(12) M(-1). These clones were found to be of IgG class and IgM class with k light chain. Subclass determination showed that the clones produced IgG(1), IgG(2a), IgG(2b), and IgM types of antibody. One clone (2H(9)) was used to establish the calibration curve with a sensitivity of 26 ng/mL, a practical working range of 46.8-6000 ng/mL parathion.

Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).