A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma.

OBJECTIVE: Diffuse midline glioma, H3 K27-altered (DMG) is a lethal pediatric brainstem tumor. Despite numerous efforts to improve survival benefits, its prognosis remains poor. This study aimed to design and synthesize a novel CDK4/6 inhibitor YF-PRJ8-1011, which exhibited more potent antitumor activity against a panel of patient-derived DMG tumor cells in vitro and in vivo compared with palbociclib. METHODS: Patient-derived DMG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The liquid chromatography tandem-mass spectrometry method was used to measure the activity of YF-PRJ8-1011 passing through the blood-brain barrier. DMG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011. RESULTS: The results showed that YF-PRJ8-1011 could inhibit the growth of DMG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood-brain barrier. It also significantly inhibited the growth of DMG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DMG in vitro and in vivo compared with palbociclib. In addition, we also found that YF-PRJ8-1011 combined with radiotherapy also showed more significant inhibition of DMG xenograft tumor growth than radiotherapy alone. CONCLUSION: Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DMG treatment.

Double-sided optical coating of strongly curved glass by atomic layer deposition.

A reaction chamber of atomic layer deposition (ALD) was developed for simultaneous coating on the inner and outer surfaces of a large-size and strongly curved glass bowl. The inner surface ALD process was in a showerhead reaction mode and the outer surface ALD process was in a cross-flow reaction mode. Blue reflection (BR) film of 400 nm wavelength and broadband antireflection (BBAR) film of 400-700 nm wavelength were coated on different glass bowls by ALD. The spectral uniformity of both coated bowls was studied. The measured spectra at multiple positions of the glass bowl with the BBAR coating show better spectral uniformity along the circumference than the depth. The spectral deviation is mainly caused by the non-uniformity of the film on the outer surface (<±3%), and the film on the inner surface has good uniformity along both the circumference and the depth (<±0.7%). The growth rate of the outer film was reduced by 10% on average compared to that of the inner film due to the different gas flow mode.

HVCMM: A Hybrid-View Abstractive Model of Automatic Summary Generation for Teaching.

With the continuous development of educational informatization, more and more emerging technologies are applied in teaching activities. These technologies provide massive and multidimensional information for teaching research, but at the same time, the information obtained by teachers and students presents an explosive increase. Extracting the core content of the class record text through text summarization technology to generate concise class minutes can significantly improve the efficiency of teachers and students to obtain information. This article proposes a hybrid-view class minutes automatic generation model (HVCMM). The HVCMM model uses a multilevel encoding strategy to encode the long text of the input class records to avoid memory overflow in the calculation after the long text is input into the single-level encoder. The HVCMM model uses the method of coreference resolution and adds role vectors to solve the problem that the excessive number of participants in the class may lead to confusion about the referential logic. Machine learning algorithms are used to analyze the topic and section of the sentence to capture structural information. We test the HVCMM model on the Chinese class minutes dataset (CCM) and the augmented multiparty interaction (AMI) dataset, and the results show that the HVCMM model outperforms other baseline models on the ROUGE metric. With the help of the HVCMM model, teachers can improve the efficiency of reflection after class and improve the teaching level. Students can review the key content to strengthen their understanding of what they have learned with the help of the class minutes automatically generated by the model.

Anti-tumor efficacy of anti-GD2 CAR NK-92 cells in diffuse intrinsic pontine gliomas.

Background: Diffuse intrinsic pontine gliomas (DIPGs) are rare and fatal pediatric brainstem gliomas with no cure. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have been proven effective in treating glioblastoma (GBM) in preclinical studies. However, there are no relevant studies on the CAR-NK treatment for DIPG. Our study is the first to evaluate the anti-tumor activity and safety of GD2-CAR NK-92 cells treatment for DIPG. Methods: Five patient-derived DIPG cells and primary pontine neural progenitor cell (PPC) were used to access disialoganglioside GD2 expression. Cell killing activity of GD2-CAR NK-92 cells was analyzed by in vitro cytotoxicity assays. Two DIPG patient-derived xenograft models were established to detect the anti-tumor efficacy of GD2-CAR NK-92 cells in vivo. Results: Among the five patient-derived DIPG cells, four had high GD2 expression, and one had low GD2 expression. In in vitro assays, GD2-CAR NK-92 cells could effectively kill DIPG cells with high GD2 expression while having limited activity against DIPG cells with low GD2 expression. In in vivo assays, GD2-CAR NK-92 cells could inhibit tumor growth in TT150630 DIPG patient-derived xenograft mice (high GD2 expression) and prolong the overall survival of the mice. However, GD2-CAR NK-92 showed limited anti-tumor activity for TT190326DIPG patient-derived xenograft mice (low GD2 expression). Conclusion: Our study demonstrates the potential and safety of GD2-CAR NK-92 cells for adoptive immunotherapy of DIPG. The safety and anti-tumor effect of this therapy need to be further demonstrated in future clinical trials.

Effects of Acute Hypoxic Stress on Physiological and Hepatic Metabolic Responses of Triploid Rainbow Trout (Oncorhynchus mykiss).

This experiment simulated the hypoxic environment caused by actual production operations in fish farming (i.e., catching, gathering, transferring, and weighting) to study the effects of acute hypoxic conditions on the physiological and metabolic responses of triploid rainbow trout (O. mykiss). Two groups of fish weighting 590 g were sampled in the normoxia group (dissolved oxygen above 7 mg/L) and hypoxia group (dissolved oxygen ranged from 2 to 5 mg/L for 10 min). The results showed that 1) regarding stress response, hypoxia increased plasma levels of cortisol, heat shock protein 70 (HSP-70), lysozyme, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine phosphokinase (CPK); induced the expression of hepatic genes encoding nuclear factor erythroid 2 related factor 2 (Nrf2), interferon γ (IFN-γ) and interleukin-1ß (IL-1ß). 2) Regarding metabolism response, hypoxia increased plasma levels of globulin (GLOB), glucose (GLU), triglyceride (TG) and lactate dehydrogenase (LDH); upregulated the hepatic gene expression of phosphoenolpyruvate carboxykinase, (PEPCK), pyruvate dehydrogenase kinase (PDK1), acetyl-CoA carboxylase (ACC) and acetyl-CoA oxidase (ACO); downregulated the hepatic gene expression of carnitine palmitoyl transferase 1 (CPT1); and unchanged the expression of hepatic genes in glycolysis and autophagy. 3) In response to hypoxia-inducible factors (HIFs), the hepatic HIF-2α gene was activated in the hypoxia group, but HIF-1α gene expression remained unchanged. Thus, during acute hypoxic stress, triploid rainbow trout were in a defensive state, with an enhanced immune response and altered antioxidant status. Additionally, the hepatic mitochondrial oxidation of glucose- and lipid-derived carbon in trout was suppressed, and hepatic gluconeogenesis and lipid synthesis were activated, which might be regulated by the HIF-2α pathway.

Prevalence and genetic diversity of Echinorhynchus gymnocyprii (Acanthocephala: Echinorhynchidae) in schizothoracine fishes (Cyprinidae: Schizothoracinae) in Qinghai-Tibetan Plateau, China.

BACKGROUND: The schizothoracine fishes, an excellent model for several studies, is a dominant fish group of the Qinghai-Tibet Plateau (QTP). However, species populations have rapidly declined due to various factors, and infection with Echinorhynchus gymnocyprii is cited as a possible factor. In the present study, the molecular characteristics of E. gymnocyprii in four species of schizothoracine fishes from the QTP were explored. METHODS: We investigated the infection status of E. gymnocyprii in 156 schizothoracine fishes from the upper Yangtze River, upper Yellow River, and Qinghai Lake in Qinghai Province, China. The complete internal transcribed spacer (ITS) of the ribosomal RNA (rRNA) gene and part of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of 35 E. gymnocyprii isolates from these fishes were sequenced and their characteristics analyzed. In addition, we inferred phylogenetic relationships of the E. gymnocyprii populations based on the rRNA-ITS and cox1 sequences. RESULTS: The total prevalence of E. gymnocyprii in schizothoracine fishes was 57.69% (90/156). However, the prevalence among different species as well as that across the geographical locations of the schizothoracine fishes was significantly different. The results of sequence analysis showed that the four E. gymnocyprii populations from different hosts and regions of Qinghai Province were conspecific, exhibiting rich genetic diversity. Phylogenetic analysis based on rRNA-ITS and cox1 sequences supported the coalescence of branches within E. gymnocyprii; the cox1 gene of E. gymnocyprii populations inferred some geographical associations with water systems. In addition, three species of schizothoracine fishes were recorded as new definitive hosts for E. gymnocyprii. CONCLUSIONS: To the best of our knowledge, this is the first molecular description of E. gymnocyprii populations in schizothoracine fishes from the Qinghai-Tibet Plateau that provides basic data for epidemiological surveillance and control of acanthocephaliasis to protect endemic fish stocks.

Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies.

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.