Two new chemical constituents from the aerial parts of Tripterygium wilfordii.

Tripterygium wilfordii has been historically employed as a conventional botanical insecticide and a plant of medicinal significance. A new dihydroagarofuran sesquiterpene (1) and a new acyclic compound (2), along with seven known compounds (3-9), have been isolated from the aerial parts of Tripterygium wilfordii. The identification of the structures of novel compounds were accomplished through comprehensive spectroscopic analyses, encompassing HRESIMS, NMR, UV, IR, and a comparative analysis with spectroscopic data from compounds previously characterised. In in-vitro bioassay, compound 8 exhibited significant inhibitory activity for NO release in LPS-induced RAW 264.7 cells, with an IC50 value of 15.7 µM.

Mi-2ß promotes immune evasion in melanoma by activating EZH2 methylation.

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2ß as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2ß rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2ß controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2ß binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2ß-targeted inhibitor, Z36-MP5, which reduces Mi-2ß ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

Arbitrary fabrication of complex lithium niobate three-dimensional microstructures for second harmonic generation enhancement.

Lithium niobate (LN) crystal plays important roles in future integrated photonics, but it is still a great challenge to efficiently fabricate three-dimensional micro-/nanostructures on it. Here, a femtosecond laser direct writing-assisted liquid back-etching technology (FsLDW-LBE) is proposed to achieve the three-dimensional (3D) microfabrication of lithium niobate (LN) with high surface quality (Ra = 0.422 nm). Various 3D structures, such as snowflakes, graphic arrays, criss-cross arrays, and helix arrays, have been successfully fabricated on the surface of LN crystals. As an example, a microcone array was fabricated on LN crystals, which showed a strong second harmonic signal enhancement with up to 12 times bigger than the flat lithium niobate. The results indicate that the method provides a new approach for the microfabrication of lithium niobate crystals for nonlinear optics.

[Molecular identification of animal species of Bufonis Venenum from secretions].

The animal species is one of the key factors affecting the quality of Bufonis Venenum. The quality of Bufonis Venenum derived from Bufo bufo gargarizans is significantly higher than that from B. melanostictus. Since Bufonis Venenum is from secretions, the conventional identification methods are difficult to identify the animal species due to the lack of the appearance and morphology of the animals. The rapid development of molecular identification technology has provided new methods for the identification of Bufonis Venenum. However, because of the low content and serve degradation of residual DNA in secretions, the research on the molecular identification of Chinese medicinal materials from secretions remains to be carried out. To understand the animal species of Bufonis Venenum, this study collected 83 samples of Bufonis Venenum, including 7 commercially available samples, 5 reference medicinal materials, and 71 animal samples from which Bufonis Venenum was prepared according to the method in the 2020 edition of the Chinese Pharmacopoeia. Different DNA extraction methods were used and compared, and the mitochondrial 16S rRNA gene fragments were amplified, on the basis of which the phylogenetic trees were built. Finally, molecular identification of the animal species of the samples was performed. The results showed that the DNA extracted from Bufonis Venenum by the reagent kit had good quality, and 16S rRNA sequences were successfully amplified from 80 out of the 83 samples. In addition, 71 16S rRNA sequences of the animal species of Bufonis Venenum were downloaded from GenBank. The phylogenetic trees constructed based on the neighbor-joining(NJ) method and the Bayesian inference(BI) method showed that the samples derived from B. bufo gargarizans and B. melanostictus were clustered into separate monophyletic clades, with the support of 100%(NJ) and 1.00(BI), respectively. The animal species of both commercially available samples and reference medicinal materials were B. bufo gargarizans. In conclusion, DNA can be extracted from Bufonis Venenum derived from secretions, and the 16S rRNA gene sequences can be amplified, which can be used for molecular identification of the animal species of Bufonis Venenum. The findings provide a reference for the quality control of Bufonis Venenum and the identification of animal species of medicinal materials derived from secretions.

Study on interface engineering and chemical bonding of the ReS2@ZnO heterointerface for efficient charge transfer and nonlinear optical conversion efficiency.

Rhenium sulfide (ReS2) has emerged as a promising two-dimensional material, demonstrating broad-spectrum visible absorption properties that make it highly relevant for diverse optoelectronic applications. Manipulating and optimizing the pathway of photogenerated carriers play a pivotal role in enhancing the efficiency of charge separation and transfer in novel semiconductor composites. This study focuses on the strategic construction of a semiconductor heterostructure by synthesizing ZnO on vacancy-containing ReS2 (VRe-ReS2) through chemical bonding processes. The ingeniously engineered built-in electric field within the heterostructure effectively suppresses the recombination of photogenerated electron-hole pairs. A direct and well-established interfacial connection between VRe-ReS2 and ZnO is achieved through a robust Zn-S bond. This distinctive bond configuration leads to enhanced nonlinear optical conversion efficiency, attributed to shortened carrier migration distances and accelerated charge transfer rates. Furthermore, theoretical calculations unveil the superior chemical interactions between Re vacancies and sulfide moieties, facilitating the formation of Zn-S bonds. The photoluminescence (PL) intensity is increased by the formation of VRe-ReS2 and ZnO heterostructure and the PL quantum yield of VRe-ReS2 is improved. The intricate impact of the Zn-S bond on the nonlinear absorption behavior of the VRe-ReS2@ZnO heterostructure is systematically investigated using femtosecond Z-scan techniques. The charge transfer from ZnO to ReS2 defect levels induces a transition from saturable absorption to reverse saturable absorption in the VRe-ReS2@ZnO heterostructure. Transient absorption measurements further confirm the presence of the Zn-S bond between the interfaces, as evidenced by the prolonged relaxation time (τ3) in the VRe-ReS2@ZnO heterostructure. This study offers valuable insights into the rational construction of heterojunctions through tailored interfacial bonding and surface/interface charge transfer pathways. These endeavors facilitate the modulation of electron transfer dynamics, ultimately yielding superior nonlinear optical conversion efficiency and effective charge regulation in optoelectronic functional materials.

Defect and interface/surface engineering synergistically modulated electron transfer and nonlinear absorption properties in MoX2 (X = Se, S, Te)@ZnO heterojunction.

Systematic interface and defect engineering strategies have been demonstrated to be an effective way to modulate the electron transfer and nonlinear absorption properties in semiconductor heterojunctions. However, the role played by defects and interfacial strain in electron transfer at the interface of the MoX2 (X = Se, S, Te)@ZnO heterojunction remains poorly understood. Herein, using the MoX2@ZnO heterojunction, we reveal that vacancies play a critical role in the interfacial electron transfer of heterojunctions. Specifically, we present the defect and interface engineering of the MoX2@ZnO heterojunction for controlled charge transfer and electron excitation-relaxation. The experimental characterization combined with first-principles calculations showed that the presence of defects promoted the transport of photogenerated carriers at the heterojunction interface, thereby inhibiting their rapid recombination. The DFT calculation confirmed that the electron band structure, density of states and charge density distribution in the system changed after the formation of Mo-O bonds. On the basis of defects and interfacial stress and the effective charge transfer, the MoX2@ZnO heterojunction exhibited excellent excitation and emission behaviors. The nonlinear optical regulation behavior of TMDs is expected to be realized with the help of the defects and interface/surface synergistically modulated effect of ZnO nanoparticles. The local strain generation on the MoX2@ZnO heterojunction boundary provides a new method for the design of new heterogeneous materials and will be of great significance to investigate the contact physical behavior and application of metals and two-dimensional (2D) semiconductors. This work provides some inspiration for the construction of heterojunctions with rich defects and surface/interface charge transfer channels to promote tunable electron transfer dynamics, thereby achieving a good nonlinear optical conversion efficiency and efficient charge separation in optoelectronic functional materials.

An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L.

FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem duplication (ITD) mutations in the juxtamembrane region. Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. Midostaurin is a first-generation FLT3 inhibitor with minimal activity as monotherapy. Midostaurin lacks selectivity and is only approved by the USFDA for use in combination with other chemotherapy agents. The second-generation inhibitors quizartinib and gilteritinib display improved specificity and selectivity, and have been approved for use as monotherapy. However, their clinical efficacies are limited in part due to the emergence of drug-resistant FLT3 secondary mutations in the tyrosine kinase domain at positions D835 and F691. Therefore, in order to overcome drug resistance and further improve outcomes, new compounds targeting FLT3-ITD with secondary mutants are urgently needed. In this study, through the structural modification of a reported compound Ling-5e, we identified compound 24 as a FLT3 inhibitor that is equally potent against FLT3-ITD and the clinically relevant mutants FLT3-ITD/D835Y, and FLT3-ITD/F691L. Its inhibitory effects were demonstrated in both cell viability assays and western blots analyses. When tested against cell lines lacking activating mutations in FLT3, no non-specific cytotoxicity effect was observed. Interestingly, molecular docking results showed that compound 24 may adopt different binding conformations with FLT3-F691L compared to FLT3, which may explain its retained activity against FLT3-ITD/F691L. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.

N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants.

Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.

Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

[Effect of Xiaoxuming Decoction on activation of astrocytes in acute cerebral ischemia/reperfusion injury].

This study investigated the effect of Xiaoxuming Decoction(XXMD) on the activation of astrocytes after cerebral ischemia/reperfusion(I/R) injury. The model of cerebral IR injury was established using the middle cerebral artery occlusion method. Fluorocitrate(FC), an inhibitor of astrocyte activation, was applied to inhibit astrocyte activation. Rats were randomly divided into a sham group, a model group, a XXMD group, a XXMD+FC group, and a XXMD+Vehicle group. Neurobehavioral changes at 24 hours after cerebral IR injury, cerebral infarction, histopathological changes observed through HE staining, submicroscopic structure of astrocytes observed through transmission electron microscopy, fluorescence intensity of glial fibrillary acidic protein(GFAP) and thrombospondin 1(TSP1) measured through immunofluorescence, and expression of GFAP and TSP1 in brain tissue measured through Western blot were evaluated in rats from each group. The experimental results showed that neurobehavioral scores and cerebral infarct area significantly increased in the model group. The XXMD group, the XXMD+FC group, and the XXMD+Vehicle group all alleviated neurobehavioral changes in rats. The pathological changes in the brain were evident in the model group, while the XXMD group, the XXMD+FC group, and the XXMD+Vehicle group exhibited milder cerebral IR injury in rats. The submicroscopic structure of astrocytes in the model group showed significant swelling, whereas the XXMD group, the XXMD+FC group, and XXMD+Vehicle group protected the submicroscopic structure of astrocytes. The fluorescence intensity and protein expression of GFAP and TSP1 increased in the model group compared with those in the sham group. However, the XXMD group, the XXMD+FC group, and XXMD+Vehicle group all down-regulated the expression of GFAP and TSP1. The combination of XXMD and FC showed a more pronounced effect. These results indicate that XXMD can improve cerebral IR injury, possibly by inhibiting astrocyte activation and down-regulating the expression of GFAP and TSP1.

Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML.

M6A (N6-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified DDO-2728 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. DDO-2728 was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. DDO-2728 increased the abundance of m6A modifications in AML cells, reduced the mRNA stability of TACC3, and inhibited cell cycle progression. Furthermore, DDO-2728 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.

Different Sources of Bone Marrow Mesenchymal Stem Cells: A Comparison of Subchondral, Mandibular, and Tibia Bone-derived Mesenchymal Stem Cells.

BACKGROUND: Stem cell properties vary considerably based on the source and tissue site of mesenchymal stem cells (MSCs). The mandibular condyle is a unique kind of craniofacial bone with a special structure and a relatively high remodeling rate. MSCs here may also be unique to address specific physical needs. OBJECTIVE: The aim of this study was to compare the proliferation and multidirectional differentiation potential among MSCs derived from the tibia (TMSCs), mandibular ramus marrow (MMSCs), and condylar subchondral bone (SMSCs) of rats in vitro. METHODS: Cell proliferation and migration were assessed by CCK-8, laser confocal, and cell scratch assays. Histochemical staining and real-time PCR were used to evaluate the multidirectional differentiation potential and DNA methylation and histone deacetylation levels. RESULTS: The proliferation rate and self-renewal capacity of SMSCs were significantly higher than those of MMSCs and TMSCs. Moreover, SMSCs possessed significantly higher mineralization and osteogenic differentiation potential. Dnmt2, Dnmt3b, Hdac6, Hdac7, Hdac9, and Hdac10 may be instrumental in the osteogenesis of SMSCs. In addition, SMSCs are distinct from MMSCs and TMSCs with lower adipogenic differentiation and chondrogenic differentiation potential. The multidirectional differentiation capacities of TMSCs were exactly the opposite of those of SMSCs, and the results of MMSCs were intermediate. CONCLUSION: This research offers a new paradigm in which SMSCs could be a useful source of stem cells for further application in stem cell-based medical therapies due to their strong cell renewal and osteogenic capacity.

Influence of hypoxia on retinal progenitor and ganglion cells in human induced pluripotent stem cell-derived retinal organoids.

AIM: To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs). METHODS: The hiPSC and a three-dimensional culture method were used for the experiments. Generated embryoid bodies (EBs) were randomly and equally divided into hypoxic and normoxic groups. Photographs of the EBs were taken on days 38, 45, and 52, and the corresponding volume of EBs was calculated. Simultaneously, samples were collected at these three timepoints, followed by fixation, sectioning, and immunofluorescence. RESULTS: The proportion of Ki67-positive proliferating cells increased steadily on day 38; this proliferation-promoting effect tended to increase tissue density rather than tissue volume. On days 45 and 52, the two groups had relatively similar ratios of Ki67-positive cells. Further immunofluorescence analysis showed that the ratio of SOX2-positive cells significantly increased within the neural retina on day 52 (P<0.05). In contrast, the percentage of PAX6- and CHX10-positive cells significantly decreased following hypoxia treatment at all three timepoints (P<0.01), except for CHX10 at day 45 (P>0.05). Moreover, the proportion of PAX6-/TUJ1+ cells within the neural retinas increased considerably (P<0.01, <0.05, <0.05 respectively). CONCLUSION: Low oxygen promotes stemness and proliferation of neural retinas, suggesting that hypoxic conditions can enlarge the retinal progenitor cell pool in hiPSC-derived ROs.

Bioinformatic analysis and verification of a lipid metabolism-related long noncoding RNA prognostic signature for head and neck squamous cell carcinoma.

PURPOSE: Both lipid metabolism reprogramming and lncRNAs exert effects on tumor development. We aimed to predict the prognosis of head and neck squamous cell carcinoma (HNSCC) based on lipid metabolism-related (LR)-lncRNAs. METHODS: LR-lncRNAs were determined from the RNA-ref profiles of HNSCC samples in The Cancer Genome Atlas (TCGA). The prognostic model was established by univariate Cox and Lasso regression analysis. Clinical relevance and predictive accuracy were investigated, and external validation was also performed in the Gene Expression Omnibus (GEO) cohort. Tumor immune infiltration and relevant functional analysis, including the association of autophagy with prognostic signatures, were conducted through single-sample gene set enrichment analysis (ssGSEA). The regulatory network of candidate LR-lncRNAs was investigated via coexpression, ceRNA and cis/trans acting interactions. Potential genes were selected through qRT-PCR analysis, and their effects on tumor biological activities and autophagic activity were explored after gene knockdown. RESULTS: A total of 222 LR-lncRNAs were identified. Among the 41 genes with prognostic significance, 17 lncRNAs were eligible for the risk model. Patients in the high-risk group had a poorer prognosis than those in the low-risk group, and the risk score was found to be positively associated with tumor microenvironment infiltration via multiple algorithms. Furthermore, improved prognosis was found in patients with high autophagic scores and low risk scores, and autophagy-related genes such as PINK1 and CCL2 showed significantly lower expression in the low-risk group. The expression of immune checkpoint genes such as CD28, CTLA4 and PDCD1 decreased dramatically in the high-risk group. The target genes of candidate lncRNAs were confirmed, such as ENO2 and PPAR-gamma. Furthermore, MIR4435-2HG was the most significantly overexpressed lncRNA in HNSCC cell lines and tumor samples, which could promote proliferation and migration and inhibit apoptosis. Additionally, MIR4435-2HG silencing activated autophagy by increasing LC3B expression. CONCLUSION: This study constructed an LR-lncRNA prognostic signature for HNSCC and indicated its relationships with tumor immunity and autophagy, which provides a promising future for LR-lncRNA-oriented prognostic tools and therapeutic targets.

Phytochemical Cue for the Fitness Costs of Herbicide-Resistant Weeds.

Despite increasing knowledge of the fitness costs of viability and fecundity involved in the herbicide-resistant weeds, relatively little is known about the linkage between herbicide resistance costs and phytochemical cues in weed species and biotypes. This study demonstrated relative fitness and phytochemical responses in six herbicide-resistant weeds and their susceptible counterparts. There were significant differences in the parameters of viability (growth and photosynthesis), fecundity fitness (flowering and seed biomass) and a ubiquitous phytochemical (-)-loliolide levels between herbicide-resistant weeds and their susceptible counterparts. Fitness costs occurred in herbicide-resistant Digitaria sanguinalis and Leptochloa chinensis but they were not observed in herbicide-resistant Alopecurus japonicas, Eleusine indica, Ammannia arenaria, and Echinochloa crus-galli. Correlation analysis indicated that the morphological characteristics of resistant and susceptible weeds were negatively correlated with (-)-loliolide concentration, but positively correlated with lipid peroxidation malondialdehyde and total phenol contents. Principal component analysis showed that the lower the (-)-loliolide concentration, the stronger the adaptability in E. crus-galli and E. indica. Therefore, not all herbicide-resistant weeds have fitness costs, but the findings showed several examples of resistance leading to improved fitness even in the absence of herbicides. In particular, (-)-loliolide may act as a phytochemical cue to explain the fitness cost of herbicide-resistant weeds by regulating vitality and fecundity.

Characteristics, differential diagnosis, individualized treatment, and prevention of hyperhomocysteinemia in newborns.

OBJECTIVES: This study aimed to investigate the incidence rate, clinical phenotype, gene variation spectrum, and prognosis of neonatal hyperhomocysteinemia (HHcy) and explore its diagnosis, individualised treatment, and prevention strategies. METHODS: We screened 84722 neonates for HHcy using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with biochemical detection, urine gas chromatography-mass spectrometry (GC-MS), and next-generation sequencing (NGS) for gene analysis to comprehensively differentiate and diagnose diseases. RESULTS: 18 children (P1-P18) were diagnosed with methylmalonic acidemia (MMA) and HHcy, and fourteen known and one new variant of the MMACHC gene were found. Five children showed poor mental reactions, brain dysplasia, lethargy, hyperbilirubinemia, and jaundice, whereas the other 13 children had no evident abnormalities. These children were all cobalamin- and folic acid-reactive types, and they were mainly supplemented with cobalamin, L-carnitine, betaine, and folic acid. The mother of P12 had a prenatal diagnosis at the next pregnancy; the results showed that MMACHC gene was not pathogenic and she gave birth to a healthy baby. One child (P19) was diagnosed with methylenetetrahydrofolate reductase (MTHFR) deficiency, and one new mutation was detected in the MTHFR gene. Patient P19 showed congenital brain dysplasia, neonatal anaemia, and hyperbilirubinemia, and treatment consisted mainly of betaine and cobalamin supplementation. One child (P20) was confirmed to have methionine adenosyltransferase I (MAT I) deficiency but had no clinical manifestations. After treatment, all the children had a good prognosis. CONCLUSION: The incidence of neonatal HHcy in the Zibo area was 1/4236, and the common pathogenic variants were c.609G>A, c.80A>G, and c.482G>A in the MMACHC gene. Patients with HHcy can achieve a good prognosis if pathogenic factors and targeted treatment are identified. Gene analysis and prenatal diagnosis contribute to the early prevention of HHcy.

Safety and efficacy of endoscopic retrograde cholangiopancreatography in previously treated liver cancer patients: a survival analysis.

Background and Aim: The prognosis and medication response for liver malignancies are both dismal and highly heterogeneous. For this diverse malignancy, multimodality therapies such as drugs, surgical management, and/or l+iver transplantation are available. Biliary complications remain a major problem after liver cancer treatment especially in those patients who undergo liver transplantation for their end stage liver disease. Although, most biliary complications can be successfully managed with endoscopic retrograde cholangiopancreatography. However, biliary complications still considered an important factor influencing long-term results in liver cancer treatment patients. The aim of this study was to evaluate the effect of biliary complications on the overall patient's survival rate after the endoscopic retrograde cholangiopancreatography. Patients and Methods: We retrospectively analyzed data of consecutive patients who were treated for liver cancer at our tertiary care hospital from January 2015 to July 2020. We focused on the biliary complications and procedural data, including post-endoscopic retrograde cholangiopancreatography complications, survival rate, and complementary or alternative treatments to endoscopic retrograde cholangiopancreatography. Results: We identified 967 cases (mean age 49; range 11-75), 84% men. During the mean follow up of 25 months (range 1 to 66 months), 102 patients developed biliary complications; 68/102 underwent 141 therapeutics endoscopic retrograde cholangiopancreatography procedures. The rest 34/102 patients were managed with percutaneous transhepatic cholangiography, conservative management, and/or surgery. Post- endoscopic retrograde cholangiopancreatography complications occurred in 79.4%, including anastomotic strictures in 25, non-anastomotic strictures in 5, stones in 5, cholangitis in 4, post-sphinctretomy bleeding in 3, pancreatitis in 2, and bile leakage in 1 patient. Seven (13.0%) patients died after ERCP due to multiple organ dysfunction syndrome. Although the survival rate of patients who underwent ERCP and those without ERCP was similar, patients with biliary complications fared significant worse. Conclusion: Although endoscopic retrograde cholangiopancreatography is useful for the management of post liver cancer treatment biliary complications; the need for multiple rounds of endoscopic retrograde cholangiopancreatography and even post endoscopic retrograde cholangiopancreatography complications is relatively high, and often results in increased mortality. However, the survival following endoscopic or surgical therapy in liver cancer treatment patients is similar.

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.

Circadian rhythm as a key player in cancer progression as well as a therapeutic target in HER2-positive advanced gastric cancer treatment.

Gastric cancer is one of the most common cancer types with less than one year prognosis in metastatic disease, which poses a huge disease burden. One of the key players in poor prognosis is human epidermal growth factor receptor 2 (HER2), which also contributes to the pathogenesis of HER2-positive advanced gastric cancer. Trastuzumab is used as first-line chemotherapy that targets the expression of HER2, however, trastuzumab resistance is an inevitable major problem. To overcome this problem, readjustment of the circadian system may play a crucial role, as dysregulation in the expression of circadian clock genes has been observed in tumors. Therefore, pharmacological modulation of clock components can be considered for better efficacy of trastuzumab. In this review, we discuss the association of circadian clock with cancer progression, development, and treatment. Metformin-based chronotherapy can disrupt BMAL1-CLOCK-PER1-HK2 axis, thereby affecting glycolysis oscillation to overcome trastuzumab resistance in HER2-positive advanced gastric cancer.

Failure of enhanced recovery after surgery in liver surgery: a systematic review and meta analysis.

Purpose: This study aimed to conduct a systematic review of the literature to identify and summarize the existing evidence regarding ERAS failure and related risk factors after hepatic surgery. The objective was to provide physicians with a better understanding of these factors so that they can take appropriate action to minimize ERAS failure and improve patient outcomes. Method: A literature search of the PubMed MEDLINE, OVID, EMBASE, Cochrane Library, and Web of Science was performed. The search strategy involved terms related to ERAS, failure, and hepatectomy. Result: A meta-analysis was conducted on four studies encompassing a total of 1,535 patients, resulting in the identification of 20 risk factors associated with ERAS failure after hepatic surgery. Four of these risk factors were selected for pooling, including major resection, ASA classification of ≥3, advanced age, and male gender. Major resection and ASA ≥ 3 were identified as statistically significant factors of ERAS failure. Conclusion: The comprehensive literature review results indicated that the frequently identified risk factors for ERAS failure after hepatic surgery are linked to operative and anesthesia factors, including substantial resection and an American Society of Anesthesiologists score of 3 or higher. These insights will assist healthcare practitioners in taking prompt remedial measures. Nevertheless, there is a requirement for future high-quality randomized controlled trials with standardized evaluation frameworks for ERAS programs.