C2 Group Research Articles

066. Sleeve Gastrectomy Decrease of TNF-a and Increase TGF-a Gene Expression in the Abdominal Aorta of Rats with Obesity and Diabetes Mellitus

Background: Sleeve gastrectomy (SG) is one option to significantly reduce body weight while also protecting the cardiovascular system by controlling hyperglycaemia and inflammatory markers. Secretion of tumour necrosis factor (TNF)-? could induce inflammation, meanwhile, the transforming growth factor-? (TGF-?) are anti-inflammatory cytokines, both of which play a role in the process of atherosclerosis. This study aimed to analyse the effect of SG procedure on TNF-? and TGF-? gene expression in the abdominal aorta of obese and DM rats. Method: Fifteen rats were divided into 3 groups: lean-non-DM rats model (C1 group), obese-DM rats model (C2 group), and obese-DM rats model underwent SG (T group). Before and 10 days after the SG procedure, rats’ body weight and fasting blood glucose (FBG) were measured. Ten days after the procedure, TNF-? and TGF-? gene expression were also evaluated by PCR. Results: At the end of the study, mean body weight, FBG levels, and TNF-? gene expression in the C1 group (231.80±4.32 gram; 68.60±2.07 mg/dL; 1.01±0.01 rfu) and T group (232.00±5.33 gram; 114.40±3.20 mg/dL; 1.97±0.57 rfu) were significantly lower than in C2 group (264.60± 3.28 gram; 271.00±6.89 mg/dL; 224.12±47.59 rfu). TGF-? gene expression was found to be considerably higher in T group (25.62 ± 3.03 rfu) compared to C1 group (1.05 ± 0.01 rfu) and C2 group (1.63 ± 0.21 rfu). Conclusion: SG could decrease body weight and FBG, as well as TNF-? gene expression, and increase TGF-? gene expression in the abdominal aorta of rats with obesity and DM.

Exposure to copper metal enhances the tolerance of An. gambiae s.s. over multiple generations while reducing both fertility and fecundity in this primary malaria vector.

Background Anopheles s.l. displays the potential to develop tolerance to heavy metals, particularly copper, this may occur at a significant biological cost, which can adversely affect its ecological fitness. This study investigated the larval metal exposure on larval development and reproduction of An. gambiae s.s., a laboratory susceptible strain, kisumu. Methods Stage 2 larvae of Anopheles gambiae, Kisumu were exposed to C1 = 484 μg L-1, C2 = 300 μg L-1 and 0 μg L-1 (control) of copper chloride. Larval mortality, pupation time, pupation rate, gonotrophic cycle length, fecundity and fertility of larvae/adults were assessed over six generations. Results Results revealed that larval mortality rate was significantly higher in the C1 groups of each group (p = 0.000), but this mortality rate decreased over generations. Pupation time was extended to 13 and 14 days respectively for C2 and C1 groups (p = 0.000) compared to the control group. Similar results were observed for the gonotrophic cycle, which increased from 4 days at G0 to more than 6 days at generation 5 in adults of C1. The pupation rate in generation 4 (C1) and generation 5 of the same group (p = 0.000) as well as the emergence rate in generation 4 (C2, p = 0.000) and generation 5 (C1 and C2, p = 0.000) decreased significantly compared to the control group. The average number of eggs laid was lower in the test groups from generation 4 to generation 5 (C1 and C2, p = 0.00) and egg fertility was also negatively affected by exposure of the larval stage of An. gambiae s.s. to copper. Conclusion Although studies have already shown that copper induces resistance in An. gambiae s.l. to insecticides, this study has shown that this adaptation requires a non-negligible biological cost in the life of the insect.

Identification of three subtypes of ovarian cancer and construction of prognostic models based on immune-related genes

BackgroundImmunotherapy has revolutionized the treatment of ovarian cancer (OC), but different immune microenvironments often constrain the efficacy of immunotherapeutic interventions. Therefore, there is an imperative to delineate novel immune subtypes for development of efficacious immunotherapeutic strategies.MethodsThe immune subtypes of OC were identified by consensus cluster analysis. The differences in clinical features, genetic mutations, mRNA stemness (mRNAsi) and immune microenvironments were analyzed among subtypes. Subsequently, prognostic risk models were constructed based on differentially expressed genes (DEGs) of the immune subtypes using weighted correlation network analysis.ResultsOC patients were classified into three immune subtypes with distinct survival rates and clinical features. Different subtypes exhibited varying tumor mutation burdens, homologous recombination deficiencies, and mRNAsi levels. Significant differences were observed among immune subtypes in terms of immune checkpoint expression and immunogenic cell death. Prognostic risk models were validated as independent prognostic factors demonstrated great predictive performance for survival of OC patients.ConclusionIn this study, three distinct immune subtypes were identified based on gene sets related to vaccine response, with the C2 subtype exhibiting significantly worse prognosis. While no statistically significant differences in tumor mutation burden (TMB) were observed across the three subtypes, the homologous recombination deficiency (HRD) score and mRNA stemness index (mRNAsi) were notably elevated in the C2 group compared to the others. Immune infiltration analysis indicated that the C2 subtype may have an increased presence of regulatory T (Treg) cells, potentially contributing to a more favorable response to combination therapies involving PARP inhibitors and immunotherapy. These findings offer a precision medicine approach for tailoring immunotherapy in ovarian cancer patients. Moreover, the C3 subtype demonstrated significantly lower expression levels of immune checkpoint genes, a pattern validated by independent datasets, and associated with a better prognosis. Further investigation revealed that the immune-related gene FCRL5 correlates with ovarian cancer prognosis, with in vitro experiments showing that it influences the proliferation and migration of the ovarian cancer cell line SKOV3.

Two factors facilitate the cost-effective and harmless cementation of rare earth slags through MICP technology: Carbonic anhydrase bacteria and endogenous calcium ions

Microbially induced carbonate precipitation (MICP), a solidification/stabilization technique that doesn't interfere with recycling and can reduce the migration of pollutants, has been employed to cement rare earth slags (RES). Currently, the MICP process of the urease/carbonic anhydrase pathway has attracted considerable attention. However, the MICP process of the urease pathway may produce high concentrations of ammonia, which can cause secondary contamination; the addition of a calcium source (calcium chloride) may increase the cost of the treatment process. In this study, two factors, carbonic anhydrase bacteria and endogenous calcium ions (Ca²⁺), facilitated the MICP technology to cost-effectively and harmlessly cement RES and stabilize contaminants. The findings indicated that strain Z1 could utilize endogenous Ca²⁺ to cement the RES, thereby enhancing its unconfined compressive strength, reducing the disintegration rate, radiation dose, and wind erosion intensity, and facilitating the stabilization of heavy metals and radionuclides. In comparison to the CK group, the leaching concentrations of Cu2+, Pb2+, Zn2+, Cd2+, Th(Ⅳ), and U(Ⅵ) in the C1 group were reduced by 42.37 %, 20.20 %, 18.77 %, 22.53 %, 12.32 %, and 23.66 %, respectively. The treatment effect can be further enhanced by adding exogenous Ca2+. This study's findings can help reduce the potential environmental risks in the long-term sequestration of RES, while also providing technical support for the sustainable development of the rare earth industry.

Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates.

Pain sensation has predominantly mechanical modalities in many pain conditions. Mechanically activated (MA) ion channels on sensory neurons underly responsiveness to mechanical stimuli. The study aimed to address gaps in knowledge regarding MA current properties in higher order species such as non-human primates (NHP; common marmosets), and characterization of MA currents in trigeminal (TG) neuronal subtypes. We employed patch clamp electrophysiology and immunohistochemistry (IHC) to associate MA current types to different marmoset TG neuronal groups. TG neurons were grouped according to presumed marker expression, action potential (AP) width, characteristic AP features, after-hyperpolarization parameters, presence/absence of AP trains and transient outward currents, and responses to mechanical stimuli. Marmoset TG were clustered into 5 C-fiber and 5 A-fiber neuronal groups. The C1 group likely represent non-peptidergic C-nociceptors, the C2-C4 groups resembles peptidergic C-nociceptors, while the C5 group could be either cold-nociceptors or C-low-threshold-mechanoreceptors (C-LTMR). Among C-fiber neurons only C4 were mechanically responsive. The A1 and A2 groups are likely A-nociceptors, while the A3-A5 groups probably denote different subtypes of A-low-threshold-mechanoreceptors (A-LTMRs). Among A-fiber neurons only A1 was mechanically unresponsive. IHC data was correlated with electrophysiology results and estimates that NHP TG has ∼25% peptidergic C-nociceptors, ∼20% non-peptidergic C-nociceptors, ∼30% A-nociceptors, ∼5% C-LTMR, and ∼20% A-LTMR. Overall, marmoset TG neuronal subtypes and their associated MA currents have common and unique properties compared to previously reported data. Findings from this study could be the basis for investigation on MA current sensitizations and mechanical hypersensitivity during head and neck pain conditions.

Comparison of the ED50 of Ciprofol Combined With or Without Fentanyl for Laryngeal Mask Airway Insertion in Children: A Prospective, Randomized, Open-Label, Dose-Response Trial.

This study aimed to estimate the effect of different doses of fentanyl on the median effective dose (ED50) of ciprofol for attenuating the airway and motor response to laryngeal mask airway (LMA) insertion response in healthy children. 90healthy preschool patients undergoing inguinal hernia repair surgery were randomly assigned to one of three groups: C0 (ciprofol+saline), C1 (ciprofol + fentanyl 1µg/kg), C2 (ciprofol + fentanyl 2µg/kg). Anesthesia was induced with either prepared fentanyl or saline, followed by ciprofol. The dose of ciprofol for each patient was determined using the up-and-down sequential study design. The primary outcome was the ED50 of ciprofol required for smooth LMA insertion in the three groups. Additionally, the time to loss of consciousness and any perioperative adverse events were recorded. Compared with the C0 group, the ED50 (95% confidence interval) of ciprofol in the C1 and C2 groups were significantly lower (1.81 [1.73-1.90]mg/kg versus 0.67 [0.64-0.71]mg/kg and 0.48 [0.42-0.54] mg/kg, respectively; P<0.05). Additionally, the ED50 of ciprofol in the C2 group was lower than that in the C1 group (0.42 [0.42-0.54] mg/kg vs 0.67 [0.64-0.71]mg/kg; P<0.05). Furthermore, the time to loss of consciousness in the C1 and C2 groups decreased by 60% and 53%, respectively, compared to the C0 group. There were no significant differences in the incidence of drug-related hypotension after anesthesia induction among the three groups. No adverse events of hypoxia, bradycardia, or injection pain were observed in any groups. In healthy, non-obese Chinese children undergoing elective inguinal hernia repair surgery, fentanyl 1µg/kg and 2µg/kg before ciprofol injection significantly reduced the ED50 of ciprofol for attenuating LMA response, with minimal occurrence of severe side effects.

Four versus six cycles of platinum-based chemotherapy for advanced Urothelial carcinoma in the era of immune checkpoint inhibitors: A retrospective cohort study (FOCUS, KCSG-GU23-08)

IntroductionThis study aimed to assess the survival outcomes of four versus six cycles of first-line platinum-based chemotherapy (PBCT) in the era of immune checkpoint inhibitor (ICI) for patients with advanced urothelial carcinoma (UC). Patients and MethodsPatients with histologically confirmed advanced UC were allocated to either the 4-cycle PBCT (C4) or 6-cycle PBCT (C6) groups and retrospectively analyzed. After the planned cycles, active surveillance was conducted every 6–8 weeks, followed by second-line treatments, including ICIs, upon progression. The primary endpoint was overall survival (OS). ResultsOf the 161 patients initiated with PBCT between September 2016 and February 2023, 27 were deemed ineligible, leaving 134 patients for analysis (C4, n = 58; C6, n = 77). Baseline characteristics, including cisplatin eligibility, were similar between the groups. With a median follow-up of 23.7 months (95 % confidence interval (CI), 20.3–27.1), no significant difference was observed in OS between the C6 and C4 groups (18.7 months vs. 17.0 months; hazard ratio (HR) 1.27, P = 0.343). In multivariate analysis adjusted for sex, initial presentation, metastatic lesion, and ECOG PS, no significant difference was observed between the C6 and C4 groups (HR 1.29, 95 % CI, 0.78–2.14, P = 0.315). ConclusionsThis study showed that four cycles of PBCT do not differ from six cycles regarding OS.

Risk assessment for femoral head collapse in osteonecrosis utilizing MRI-derived large lesion ratio: a retrospective cohort study

PurposeThis study aimed to developed a novel and practical method to quantify the involvement of lesion in osteonecrosis of the femoral head (ONFH). We hypothesized that the new metric large lesion ratio (LLR) had promising prognostic value.MethodsA total of 131 hips with non-traumatic ONFH were included in this retrospective study. Patient aged 18–60 with MRI-confirmed diagnosis, and a minimum of 2-year follow-up or radiographic collapse progression during follow-up were included. Patients with prior hip surgery, incomplete data or advanced ONFH at baseline (femoral head collapse > 2 mm or osteoarthritis) were excluded. Involvement of necrotic lesion was evaluated by calculating LLR. The differences of LLR between collapse progression and non-progression groups were investigated, and the differences among different scanning parameters groups were also examined. Prognostic value of LLR was examined by multivariate regression analysis. Receiver operating characteristic curves (ROC) were constructed and areas under the curve (AUC) were compared.ResultsThe median of LLR was 66.67% in the collapse progression group, which was significantly higher compared with 25.00% in the non-progression group (P < 0.001). Subgroups analysis showed that LLR were significantly higher in the collapse progression group of Japanese Investigation Committee type C1 (P < 0.001)and C2 (P = 0.002). Multivariate regression showed that LLR were independently correlated with collapse progression (OR, 1.46 [95% CI, 1.24–1.78]; P < 0.001). ROC analysis showed that the AUC for LLR was 0.84, outperforming the 0.74 AUC OF the JIC classification.ConclusionLLR could served as a efficient tool to assess the risk of collapse progression and guide the selection of treatment strategy.

International Academy of Cytology standardized reporting of breast fine-needle aspiration cytology with cyto-histopathological correlation of breast carcinoma.

The International Academy of Cytology (IAC) has developed a standardized approach for reporting the findings of breast fine-needle aspiration cytology (FNAC). Accordingly, there are five chief categories of breast lesions, C1 (insufficient material), C2 (benign), C3 (atypical), C4 (suspicious), and C5 (malignant). The prognostication and management of breast carcinoma can be performed readily on the basis of this classification system. The aim of this study was to classify various breast lesions into one of the above-named categories and to further grade the C5 lesions specifically using the Robinson system. The latter grades were then correlated with modified Scarff-Bloom-Richardson (SBR) grades. This retrospective study was undertaken in the pathology department of a hospital located in the urban part of the city of Bangalore. All FNAC procedures performed on breast lumps spanning the year 2020 were included in the study. A total of 205 breast lesions was classified according to the IAC guidelines into C1 (6 cases, 2.9%), C2 (151 cases, 73.7%), C3 (13 cases, 6.3%), C4 (5 cases, 2.5%), and C5 (30 cases, 14.6%) groups. The C5 cases were further graded using Robinson's system. The latter showed a significant correlation with the SBR system (concordance=83.3%, Spearman correlation=0.746, Kendall's tau-b=0.736, kappa=0.661, standard error=0.095, p≤.001). A standardized approach for FNAC reporting of breast lesions, as advocated for by the IAC, improves the quality and clarity of the reports and assures diagnostic reproducibility on a global scale. Further, the cytological grading of C5 lesions provides reliable cyto-prognostic scores that can help assess a tumor's aggressiveness and predict its histological grade.

Effect of L-Citrulline on Creatine Kinase MM (CK-MM) Isoenzymes in Mice: An In Vivo Study Focusing on Immunohistochemistry Analysis

Highlights:1. This study elucidates the effect of L-citrulline supplementation on creatine kinase MM (CK-MM) expression post-eccentric exercise, offering novel insights into its potential role in mitigating muscle damage.2. The findings demonstrate that L-citrulline administration significantly reduces CK-MM expression levels in skeletal muscle tissue, suggesting its therapeutic potential in enhancing muscle recovery and performance following exercise-induced damage.3. This study contributes valuable insights into the multifaceted benefits of L-citrulline supplementation for supporting overall muscle health and performance by identifying its protective effects under different mechanisms, including improved blood flow, antioxidant activity, enhanced mitochondrial function, and promotion of muscle protein synthesis. Abstract Eccentric exercise often induces muscle injuries in athletes, resulting in impaired performance and prolonged recovery time. Creatine kinase MM (CK-MM) is a biomarker for assessing muscle damage, with elevated levels indicating injury. L-citrulline, an amino acid, has shown promise in enhancing performance and reducing recovery time. However, its specific effect on CK-MM remains unclear. This study utilized immunohistochemistry analysis to investigate the effect of L-citrulline supplementation on CK-MM expression post-eccentric exercise in male BALB/c mice. This in vivo study was conducted with a post-test-only design. A total of 25 mice were divided into two control groups (normal/C1 and negative/C2) and three treatment groups (T1, T2, and T3), each containing five mice. The T1, T2, and T3 groups were daily administered 250, 500, and 1,000 mg/kg bw of L-citrulline for seven days, respectively. All mice, except the C1 group, performed a downhill running procedure. The CK-MM expression in skeletal muscle tissue post-eccentric exercise was assessed using immunohistochemistry analysis. The statistical analysis included the Shapiro-Wilk test for data distribution and the Kruskal-Wallis and Mann-Whitney post-hoc tests for significant differences (p&lt;0.05). The results showed that CK-MM expression in the C2 group (91.00±2.24%) was significantly higher (p=0.008) than that of the C1 group (70.00±10.0%). Subsequently, the T1 (68.00±9.08%, p=0.008), T2 (72.00±7.58%, p=0.008), and T3 (67.00±9.75%, p=0.008) groups exhibited significantly lower expressions than the C2 group. These results were consistent with the role of CK-MM as a marker for muscle damage, and they indicated that L-citrulline might have a protective effect against muscle damage post-eccentric exercise. However, no significant differences were observed among the C1, T1, T2, and T3 groups. In conclusion, L-citrulline supplementation demonstrates promise in attenuating muscle damage following eccentric exercise, as evidenced by reduced CK-MM expression levels. These findings highlight the potential therapeutic role of L-citrulline in enhancing muscle recovery and performance.

Incorporation of carboxymethyl chitosan (CMCS) for the modulation of physio-chemical characteristics and cell proliferation environment of the composite hydrogel microspheres

Hydrogels have excellent swelling properties and have been widely applied in tissue engineering because of their similarity to the extracellular matrix (ECM). Sodium alginate (SA) and carboxymethyl chitosan (CMCS) were prepared into hydrogel microspheres with Ca2+crosslinking in our study. The morphology, inner structure, mechanical properties, water content, swelling rate and BMP-2 loading and releasing properties were characterized. Our results showed that the composite SA /CMCS hydrogel microspheres were translucent and spherical in shape with uniform particle size. The incorporation of CMCS further increased the diameters of the microspheres, internal pore structure, water content, and mechanical properties of the SA/CMCS hydrogel microspheres. At the same SA concentration, with the increase of CMSC concentration, the diameter of microspheres could be increased by about 0.4 mm, the water content can be increased about 1%-2%. As for the mechanical properties, the compressive strength can be increased by 0.04-0.1 MPa, and the modulus of elasticity can be increased by 0.1-0.15 MPa. BMP-2 was chosen as a model agent and it could be loaded into SA/CMCS microspheres, and the incorporation of CMCS increased BMP-2 loading. The encapsulated BMP-2 was sustainably releasedin vitro. The leaching solutions of the SA/CMCS hydrogel microspheres exhibited good cytocompatibility and could increase ALP activity, ALP expression, and biomineralization on MC3T3-E1 cells. After 7 d of co-culture, ALP activities in S2.5C2 and S2.5C3 groups was increased by 50% and 45% compared with that of the control group. When embedded in the SA/CMCS microspheres, the MC3T3-E1 cells were evenly distributed inside the hydrogel microspheres and remained viable. Transcriptomic studies showed that incorporation of CMCS induced upregulation of 1141 differentially expressed genes (DEGs) and downregulation of 1614 DEGs compared with SA microspheres. The most significantly enriched pathways were the Wnt and MAPK signaling pathways induced by the incorporation of CMCS and BMP-2. In conclusion, our results indicated that the physiochemical characteristics of the SA hydrogel microspheres could be greatly modulated by CMCS to better mimic the ECM microenvironment and induce osteo-inductive activities of MC3T3-E1 cells.

Effects of Vitamin C on the Gonad Growth, Texture Traits, Collagen Content and Synthesis Related Gene Expression of Sea Urchin (Mesocentrotus nudus).

The market value of sea urchin gonads is determined by the specific characteristics associated with gonad size and texture. Formulated feeds can effectively promote the gonad growth of sea urchins but cannot assure essential gonad texture traits. The objective of this study was to investigate the impact of vitamin C (VC) on the gonad growth, texture, collagen content, and the expression of genes involved in the collagen synthesis of sea urchins (Mesocentrotus nudus). Graded amounts of VC (0, 3000 and 6000 mg/kg) were supplemented to make three formulated feeds. Fresh kelp (Saccharina japonica) was used as the control diet. Each diet was randomly distributed to three tanks of M. nudus. The results indicated that the gonadosomatic index (GSI) and texture traits of M. nudus fed C3000 were significantly greater than those fed C0 and C6000. Collagen type I (Col I) in the gonads of M. nudus fed C3000 showed significantly greater areas than those fed C0 and C6000. Consistently, the expression levels of collagen alpha-1 (colp1α) of M. nudus fed C3000 were significantly higher than those fed C0 and C6000. As for the transforming growth factor beta (tgf-β)/Smads pathway, the expression levels of collagen synthesis genes (tgf-β receptor 1 and 2, smad nuclear-interacting protein 1 (snip1) and prolyl 4-hydroxylase subunit beta (p4hβ)) in the C3000 group were significantly greater than those in the C0, C6000 and kelp groups. On the contrary, the expression levels of collagen degradation genes (lysyl oxidase-like 2 (loxl2) and matrix metalloproteinase 14 (mmp14)) in the C3000 group were significantly lower than those in the C0, C6000 and kelp groups. In conclusion, VC at an addition level of 3000 mg/kg significantly increased the gonad texture and collagen contents of M. nudus, which could be accomplished by increasing collagen synthesis and inhibiting collagen degradation through the tgf-β/Smads pathway. These results could contribute to better understanding the beneficial effects of VC addition on the gonad texture quality of M. nudus.

Fate of heavy metals in ecosystems of dam reservoirs: Transport, distribution and significance of the origin of organic matter

In this article, a multivariate analysis of the parameters determining the transport and fate of selected heavy metals in the water - bottom sediment interface was carried out. The studies were carried out in the summer season of 2019 at Nielisz Reservoir (southeastern Poland, Lublin Voivodeship).Finally, a previously unknown factor related to the quality of organic matter was identified. Autochthonous organic matter was shown to promote the accumulation of the studied heavy metals. To date, the significance of the origin of organic matter in the context of the transport and fate of heavy metals in retention reservoirs has rarely been reported in the scientific literature. More than that, this factor was not considered an important component in the process of heavy metal deposition in bottom sediments. However, it turns out that not only the quantity of organic matter, but also its quality plays an important role in the circulation of heavy metals in retention reservoir ecosystems. It was found that autochthonous organic matter promotes the accumulation of the studied heavy metals. It can be assumed that, in a sense, it plays the role of a catenary ("hub") controlling the fate of heavy metals in the water-sediment system. It has also been conjectured that, in a sense, OMS may reflect the potential for heavy metal assimilation by aquatic vascular plants (mainly of the C3 group). Plants with a photosynthetic pathway similar to the C3 group generally have a much lower enrichment in the 13C isotope (δ13C from −38‰ to −22‰). In our case, the lowest δ13C-TOCS value was −24.05‰, and the average for the whole reservoir was −21.53‰. In addition, it was observed that quantitative changes in the isotopic composition of total organic carbon δ13C-TOCS, corresponded with changes in the content of the heavy metals studied in entrapped sediments.

Immunogenic cell death (ICD) genes predict immunotherapy response and therapeutic targets in acute myeloid leukemia (AML).

Numerous studies have demonstrated acute myeloid leukemia (AML) is one of the malignancies with high mortality worldwide. Immunogenic cell death (ICD) is a form of cell death that is specialised in that it triggers the body's immune response, particularly the adaptive immune response. Recent evidence has confirmed that pseudogenes are implicated in multiple human tumorigenesis and progression although lacking the function of coding protein. However, the roles of ICD-associated genes in AML remain largely unascertained. TCGA-AML and GSE71014 cohorts were picked out and we combined them into a merged dataset by removing the batch effect using the sva package in the R project. A consensus clustering analysis of the ICD genes in AML was performed to define subgroups. Based on the expression of 15 prognostic-related pseudogenes, we developed a prognostic model and categorized AML samples into low and high-risk groups. AML was differentiated into two subgroups (C1 and C2 clusters). Most ICD-related genes were significantly up-regulated in the C2 cluster. The single sample gene set enrichment analysis (ssGSEA) revealed that the immune cell infiltration and immune checkpoint gene expression of the C2 cluster was strongly high, suggesting that the C2 population responded well to immune checkpoint blockade (ICB) therapy and had better survival. The C1 group was sensitive to chemotherapy, including Cytarabine, Midostaurin, and Doxorubicin. On the other hand, 15 ICD-related pseudogenes were identified to be associated with AML prognosis. The receiver operator curve (ROC) analysis and nomogram manifested that our prognostic model had high accuracy in predicting survival. However, the high-risk group was sensitive to ICB therapy and chemotherapy such as Methotrexate, Cytarabine, and Axitinib while the low-risk group benefited from 5-Fluorouracil, Talazoparib, and Navitoclax therapy. In summary, we defined two subgroups relying on 33 ICD-related genes and this classification exerted a decisive role in assessing immunotherapy and chemotherapy benefit. Significantly, a prognostic signature identified by critical ICD-related pseudogene was created. The pseudogene prognostic signature had a powerful performance in predicting prognosis and therapeutic efficacy, including immunotherapy and chemotherapy to AML. Our research points out novel implications of ICD in cancer prognosis and treatment approach choice.

Evening primrose and its compounds of 1-Oxohederagenin and remangilone C ameliorate bleomycin-induced pulmonary fibrosis by regulating β-catenin signaling

BackgroundPulmonary fibrosis (PF) is a progressive and severe respiratory disease for which there is still a lack of satisfactory treatment methods other than lung transplantation. Evening primrose (EP) is widely used in Chinese folk medicinal herbs, especially for the treatment of lung-related diseases. However, the protective effect of evening primrose against PF has yet to be reported. PurposeThis study explores the pharmacological effect of EP and its possible active components against PF from the perspectives of lung function, histopathological staining, and molecular biology assays. MethodsEstablishing a rat pulmonary fibrosis model using bleomycin to detect lung function, pathological changes, and collagen deposition. TGF-β1 was used to establish an in vitro model of PF in BEAS-2B cells, and the active ingredients in evening primrose were screened. Then, the therapeutic effects of 1-Oxohederagenin (C1) and remangilone C (C2) derived from EP were observed in an in vivo model of bleomycin-induced PF, and the differentially expressed genes between the C1 and C2 treatment groups and the model group were screened with transcriptome sequencing. Finally, TGF-β1-induced damage to HFL1 cell was used to explore the specific mechanisms by which C1 and C2 alleviate PF and the involvement of β-catenin signaling. ResultsEvening primrose extract showed some ameliorative effects on bleomycin-induced PF in rats, manifested as reduced pathological damage and reduced collagen deposition. The chemical components of C1 and C2 potently ameliorated BLM-induced PF in animals and effectively inhibited fibroblast activation by interfering with β-catenin signaling. ConclusionEvening primrose extract has certain ameliorative effects on PF. In addation, C1 and C2 might be related with the suppression of fibroblast activation by inhibiting β-catenin signaling.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and β-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

New Insights into the Mechanism by Which the Pituitary Gland Copes with Hypoxia Stress Based on a Transcriptomic Analysis of Megalobrama amblycephala.

Hypoxia is a common environmental stressor in aquatic ecosystems, and during the cultivation process, Megalobrama amblycephala is prone to death because it is hypoxia-intolerant, which brings huge economic losses to farmers. The pituitary gland is a crucial endocrine gland in fish, and it is mainly involved in the secretion, storage, and regulation of hormones. In the present study, we compared the transcriptional responses to serious hypoxia in the pituitary gland among hypoxia-sensitive (HS) and hypoxia-tolerant (HT) M. amblycephala and a control group that received a normal oxygen supply (C0). The fish were categorized according to the time required to lose balance during a hypoxia treatment. A total of 129,251,170 raw reads were obtained. After raw sequence filtering, 43,461,745, 42,609,567, and 42,730,282 clean reads were obtained for the HS, HT, and C0 groups, respectively. A transcriptomic comparison revealed 1234 genes that were differentially expressed in C0 vs. HS, while 1646 differentially expressed genes were obtained for C0 vs. HT. In addition, the results for HS vs. HT showed that 367 upregulated and 41 downregulated differentially expressed genes were obtained for a total of 408 differentially expressed genes. A KEGG analysis of C0 vs. HS, C0 vs. HT, and HS vs. HT identified 315, 322, and 219 enriched pathways, respectively. Similar hypoxia-induced transcription patterns suggested that the downregulated DEGs and enriched pathways were related to pathways of neurodegeneration in multiple diseases, pathways in cancer, thermogenesis, microRNAs in cancer, diabetic cardiomyopathy, and renin secretion. However, in the upregulated DEGs, the PI3K-Akt signaling pathway (C0 vs. HS), microRNAs in cancer (C0 vs. HT), and HIF-1 signaling pathway (HS vs. HT) were significantly enriched. There is a lack of clarity regarding the role of the pituitary gland in hypoxic stress. These results not only provide new insights into the mechanism by which pituitary tissue copes with hypoxia stress in M. amblycephala but also offer a basis for breeding M. amblycephala with hypoxia-resistant traits.

Evaluation of STAT3 Inhibition by Cancer Chemopreventive Trichothecenes Derived from Metabolites of Trichothecium roseum.

This study evaluated the ability of isolated or semisynthesized trichothecene sesquiterpenes to prevent cancer emergence and proliferation and inhibit signal transducer and activator of transcription-3 (STAT3) phosphorylation through in vitro assays. Trichothecinol A (TTC-A), which bears a hydroxy group at C3, exhibited greater cancer prevention, antiproliferation, and STAT3 phosphorylation inhibition effects than trichothecin (TTC), which lacks a hydroxy group at C3. Furthermore, trichothecinol B (TTC-B), which is a reduced derivative of TTC and has similar cytotoxic effect, showed substantially weaker chemoprotection and STAT3 phosphorylation inhibition effects than TTC. These results clearly indicate that the hydroxy group at C3 and carbonyl group at C8 are crucial for inducing both potent chemoprevention and STAT3 phosphorylation inhibition.

Multistage melt/fluid modification of lithospheric mantle beneath the circum-cratonic orogenic belt: Evidence from the Tuoyun peridotite xenoliths

The juvenile and moderate refractory mantle beneath the circum-cratonic orogenic belt is traditionally believed to be hotter and thinner than the ancient refractory cratonic mantle; it is thus more unstable and subject to modification by melts/fluids. Understanding these modification processes would help to elucidate the evolution of Earth’s continents. Peridotite xenoliths carried by the Tuoyun Cenozoic lamprophyre from the southwestern Tianshan belt show evidence of widespread multistage melt/fluid modification of the unstable circum-cratonic orogenic belt mantle. Tuoyun peridotites mainly consist of moderately refractory to fertile lherzolites (Mg# in Ol: 85.5−90.7; Cr# in Sp: 12.7−26.5) and show strong mechanical modification. They can be divided into four groups (A, B, C1, and C2) based on petrography and mineral chemistry. Group A lherzolites show relatively high basaltic components (Al2O3, CaO, TiO2, and FeO) and are enriched in large ion lithophile elements (LILEs) and rare earth elements (REEs), which indicates melt-peridotite reaction processes at high melt/rock ratios. The high modal pyroxene content in Group A suggests that the addition of high-Si melts caused the transition from olivine to pyroxene. Group B lherzolites show high modal pyroxene but relatively depleted incompatible elements, which should be superimposed by later melt extraction. Comparatively, Group C lherzolites exhibit higher modal olivine but lower basaltic components. The clinopyroxene cores of Group C1 are characterized by high (La/Yb)N and low Ti/Eu content, negative high field strength element (HFSE) anomalies, and relatively high 87Sr/86Sr ratios (cores: 0.70331−0.70457), which suggest metasomatism by carbonatite melts originating from recycled sedimentary carbonate. The Group C1 clinopyroxene (spongy rims) and Group C2 clinopyroxene (cores and spongy rims) have positive Sr anomalies, depleted HFSEs, and spoon-shaped REE patterns, which suggest modification by evolved small-volume and volatile-rich silicate melts. In addition, the melt pockets around spinels and the reactive zones of pyroxenes near the lamprophyre reveal the recent incongruent dissolution induced by the host rock. Based on our research and previously reported geological data, we propose that the high-Si melts and carbonatite melts are the products of dehydration and partial melting of the Paleo-Asian oceanic crust, and lithospheric delamination and fracturing (e.g., the Talas-Fergana strike-slip fault) provided the opportunity for small-volume and volatile-rich silicate melts and basaltic melts to modify the peridotites. Multistage melts/fluids and the deformation process are the protagonists in the evolutionary process of the circum-cratonic lithospheric mantle, with important implications for mantle destabilization and multilayered interaction.

Proteomic and Phosphoproteomic analysis of thyroid papillary carcinoma: Identification of potential biomarkers for metastasis

Thyroid cancer has emerged as the most rapidly proliferating solid neoplasm. In this study, we included a cohort of patients who underwent sonographic assessment and surgical intervention at the Sir Run Run Shaw Hospital, associated with the School of Medicine at Zhejiang University, spanning from January 2019 to June 2020. Stratification of cases was based on a combination of preoperative ultrasonographic evaluations and postoperative histopathological diagnoses, resulting in three distinct groups: high-risk papillary thyroid carcinoma (PTC) labeled as C1, low-risk PTC designated as C2, and a control group (N) composed of benign thyroid tissue adjacent to the carcinoma. Proteomic and phosphoproteomic analyses were conducted on PTC specimens. The comparative assessment revealed that proteins up-regulated in the C1/N and C2/N groups were predominantly involved in functions such as amino acid binding, binding of phosphorylated compounds, and serine protease activity. Notably, proteins like NADH dehydrogenase, ATP synthase, oxidoreductases, and iron ion channels were significantly elevated in the C1 versus C2 comparative group. Through meticulous analysis of differential expression multiples, statistical significance, and involvement in metabolic pathways, this study identified eight potential biomarkers pertinent to PTC metastasis diagnostics, encompassing phosphorylated myosin 10, phosphorylated proline-directed protein kinase, leucine tRNA synthetase, 2-oxo-isovalerate dehydrogenase, succinic semialdehyde dehydrogenase, ADP/ATPtranslocase, pyruvate carboxylase, and fibrinogen. Therapeutic assays employing metformin, an AMP-activated protein kinase (AMPK) activator, alongside the phosphorylation-specific inhibitor ML-7 targeting Myosin10, demonstrated attenuated cellular proliferation, migration, and invasion capabilities in thyroid cancer cells, accompanied by a reduction in amino acid pools. Cellular colocalization and interaction studies elucidated that AMPK activation imposes an inhibitory influence on Myosin10 levels. The findings of this research corroborate the utility of proteomic and phosphoproteomic platforms in the identification of metastatic markers for PTC and suggest that modulation of AMPK activity, coupled with the inhibition of Myosin10 phosphorylation, may forge novel therapeutic avenues in the management of thyroid carcinoma. SignificanceThe significance of our research lies in its potential to transform the current understanding and management of thyroid papillary carcinoma (PTC), particularly in its metastatic form. By integrating both proteomic and phosphoproteomic analyses, our study not only sheds light on the molecular alterations associated with PTC but also identifies eight novel biomarkers that could serve as indicators of metastatic potential.