Efficacy Assessment of Post-nephrectomy Adjuvant Therapies in Patients with Renal Cell Carcinoma.

OBJECTIVE: The objective of our study was to integrate the efficacy results of post-nephrectomy adjuvant therapies in renal cell carcinoma (RCC) patients with risk of recurrence, and attempt to determine the optimal intervention choice. METHODS: We performed standard meta-analysis procedures in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed, Embase, and Cochrane Library databases were searched from inception to 22 September 2022. Randomized controlled trials reporting overall survival (OS) or disease-free survival (DFS) of adjuvant therapies, including immune checkpoint inhibitors (ICIs) and targeted therapies, in adult post-nephrectomy RCC patients were eligible for inclusion. RESULTS: Seven studies involving 7548 participants were included in our analyses. In contrast with placebo, DFS benefit with ICIs was only observed in female RCC patients and RCC patients with high programmed death-ligand 1 (PD-L1) expression (≥ 1%), sarcomatoid features, and M0 intermediate-high risk. Network meta-analyses demonstrated that pembrolizumab exhibited both DFS and OS benefit compared with placebo, sunitinib, sorafenib, and girentuximab, and only DFS benefit compared with atezolizumab and nivolumab plus ipilimumab. CONCLUSIONS: Our results suggest that post-nephrectomy RCC patients with sarcomatoid differentiation and high PD-L1 expression were more responsive to ICIs. Furthermore, pembrolizumab monotherapy exhibited superior DFS and OS results over other adjuvant therapies.

DNA Methylation-Based Diagnosis and Treatment of Breast Cancer.

DNA methylation is a key epigenetic modifier involved in tumor formation, invasion, and metastasis. The development of breast cancer is a complex process, and many studies have now confirmed the involvement of DNA methylation in breast cancer. Moreover, the number of genes identified as aberrantly methylated in breast cancer is rapidly increasing, and the accumulation of epigenetic alterations becomes a chronic factor in the development of breast cancer. The combined effects of external environmental factors and the internal tumor microenvironment promote epigenetic alterations that drive tumorigenesis. This article focuses on the relevance of DNA methylation to breast cancer, describing the role of detecting DNA methylation in the early diagnosis, prediction, progression, metastasis, treatment, and prognosis of breast cancer, as well as recent advances. The reversibility of DNA methylation is utilized to target specific methylation aberrant promoters as well as related enzymes, from early prevention to late targeted therapy, to understand the journey of DNA methylation in breast cancer with a more comprehensive perspective. Meanwhile, methylation inhibitors in combination with other therapies have a wide range of prospects, providing hope to drug-resistant breast cancer patients.

Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis.

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Advantage effect of Dalbergia pinnata on wound healing and scar formation of burns.

ETHNOPHARMACOLOGICAL RELEVANCE: Dalbergia pinnata, as a natural and ethnic medicine in China, has been used for burns and wounds with a long history, which has the effect of invigorating blood and astringent sores. However, there were no reports on the advantage activity of burns. AIM OF STUDY: The purpose of this study was to screen out the best active extract part of Dalbergia pinnata and investigate its therapeutic effect on wound healing and scar resolution. MATERIALS AND METHODS: Rat burn model was established and the healing effects of extracts from Dalbergia pinnata on burn wounds were evaluated by the percentage of wound contraction and period of epithelialization. Histological observation, immunohistochemistry, immunofluorescence and ELISA were used for the examination of inflammatory factors, TGF-ß1, neovascularization and collagen fibers through the period of epithelialization. In addition, the effect of the optimal extraction site on fibroblast cells was evaluated by cell proliferation and cell migration assays. The extracts of Dalbergia pinnata were analyzed by UPLC-Q/TOF-MS or GC-MS technique. RESULTS: Compared to the model group, there were better wound healing, suppressed inflammatory factors, more neovascularization as well as newly formed collagen in the ethyl acetate extract (EAE) and petroleum ether extract (PEE) treatment groups. The ratio of Collagen I and Collagen III was lower in the EAE and PEE treatment groups, suggesting a potential for reduced scarring. Furthermore, EAE and PEE could repair wounds by up-regulating TGF-ß1 in the early stage of wound repair and down-regulating TGF-ß1 in the late stage. In vitro studies showed that both EAE and PEE were able to promote NIH/3T3 cells proliferation and migration compared with the control group. CONCLUSIONS: In this study, EAE and PEE were found to significantly accelerate wound repair and might have an inhibitory effect on the generation of scars. It was also hypothesized that the mechanism might be related to the regulation of TGF-ß1 secretion. This study provided an experimental basis for the development of topical drugs for the treatment of burns with Dalbergia pinnata.

Two-Dimensional Carbon Graphdiyne: Advances in Fundamental and Application Research.

Graphdiyne (GDY), a rising star of carbon allotropes, features a two-dimensional all-carbon network with the cohybridization of sp and sp2 carbon atoms and represents a trend and research direction in the development of carbon materials. The sp/sp2-hybridized structure of GDY endows it with numerous advantages and advancements in controlled growth, assembly, and performance tuning, and many studies have shown that GDY has been a key material for innovation and development in the fields of catalysis, energy, photoelectric conversion, mode conversion and transformation of electronic devices, detectors, life sciences, etc. In the past ten years, the fundamental scientific issues related to GDY have been understood, showing differences from traditional carbon materials in controlled growth, chemical and physical properties and mechanisms, and attracting extensive attention from many scientists. GDY has gradually developed into one of the frontiers of chemistry and materials science, and has entered the rapid development period, producing large numbers of fundamental and applied research achievements in the fundamental and applied research of carbon materials. For the exploration of frontier scientific concepts and phenomena in carbon science research, there is great potential to promote progress in the fields of energy, catalysis, intelligent information, optoelectronics, and life sciences. In this review, the growth, self-assembly method, aggregation structure, chemical modification, and doping of GDY are shown, and the theoretical calculation and simulation and fundamental properties of GDY are also fully introduced. In particular, the applications of GDY and its formed aggregates in catalysis, energy storage, photoelectronic, biomedicine, environmental science, life science, detectors, and material separation are introduced.

Multi-heterointerfaces for selective and efficient urea production.

A major impediment to industrial urea synthesis is the lack of catalysts with high selectivity and activity, which inhibits the efficient industrial production of urea. Here, we report a new catalyst system suitable for the highly selective synthesis of industrial urea by in situ growth of graphdiyne on the surface of cobalt-nickel mixed oxides. Such a catalyst is a multi-heterojunction interfacial structure resulting in the obvious incomplete charge-transfer phenomenon between a graphdiyne and metal oxide interface and multiple intermolecular interactions. These intrinsic characteristics are the origin of the high performance of the catalyst. Studies on the mechanism reveal that the catalyst could effectively optimize the adsorption/desorption capacities of the intermediate and promote direct C-N coupling by significantly suppressing by-product reactions toward the formation of H2, CO, N2 and NH3. The catalyst can selectively synthesize urea directly from nitrite and carbon dioxide in water at room temperature and pressure, and exhibits a record-high Faradaic efficiency of 64.3%, nitrogen selectivity (Nurea-selectivity) of 86.0%, carbon selectivity (Curea-selectivity) of ∼100%, as well as urea yield rates of 913.2 µg h-1 mgcat -1 and remarkable long-term stability.

Comparative chloroplast genome analyses of Amomum: insights into evolutionary history and species identification.

BACKGROUND: Species in genus Amomum always have important medicinal and economic values. Classification of Amomum using morphological characters has long been a challenge because they exhibit high similarity. The main goals of this study were to mine genetic markers from cp genomes for Amomum species identification and discover their evolutionary history through comparative analysis. RESULTS: Three species Amomum villosum, Amomum maximum and Amomum longipetiolatum were sequenced and annotated for the complete chloroplast (cp) genomes, and the cp genomes of A. longipetiolatum and A. maximum were the first reported. Three cp genomes exhibited typical quadripartite structures with 163,269-163,591 bp in length. Each genome encodes 130 functional genes including 79 protein-coding, 26 tRNAs and 3 rRNAs genes. 113-152 SSRs and 99 long repeats were identified in the three cp genomes. By designing specific primers, we amplified the highly variable loci and the mined genetic marker ccsA exhibited a relatively high species identification resolution in Amomum. The nonsynonymous and synonymous substitution ratios (Ka/Ks) in Amomum and Alpinia showed that most genes were subjected to a purifying selection. Phylogenetic analysis revealed the evolutionary relationships of Amomum and Alpinia species and proved that Amomum is paraphyletic. In addition, the sequenced sample of A. villosum was found to be a hybrid, becoming the first report of natural hybridization of this genus. Meanwhile, the high-throughput sequencing-based ITS2 analysis was proved to be an efficient tool for interspecific hybrid identification and with the help of the chloroplast genome, the hybrid parents can be also be determined. CONCLUSION: The comparative analysis and mined genetic markers of cp genomes were conducive to species identification and evolutionary relationships of Amomum.

The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application.

Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.

Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.

An effective and recyclable decolorization method for polysaccharides from Isaria cicadae Miquel by magnetic chitosan microspheres.

The purpose of this research was to develop an efficient and non-destructive method for decolorizing of polysaccharides extracted from Isaria cicadae Miquel by magnetic chitosan microspheres (MCM). The optimum decolorization parameters were achieved by response surface methodology as follows: the MCM amount was 8.0%, the adsorption temperature was 48 °C, the adsorption time was 82 min and the pH was 7. Under these optimal conditions, the D r%, R r%, and K c were 90.31 ± 0.12%, 95.40 ± 0.11% and 19.66 ± 0.49, respectively. MCM adsorption of pigment molecules was a spontaneous and endothermic process that could be fitted with the pseudo-second-order equation and the Freundlich equation. Besides, the adsorption mechanism could be controlled by multiple-diffusion steps, including film diffusion and intra-particle diffusion. Furthermore, MCM is a recyclable material. Adsorption with MCM is a promising method to remove pigment molecules of polysaccharide, it may replace the traditional decolorization method.

Graphdiyne-based metal atomic catalysts for synthesizing ammonia.

Development of novel catalysts for nitrogen reduction at ambient pressures and temperatures with ultrahigh ammonia (NH3) yield and selectivity is challenging. In this work, an atomic catalyst with separated Pd atoms on graphdiyne (Pd-GDY) was synthesized, which shows fascinating electrocatalytic properties for nitrogen reduction. The catalyst has the highest average NH3 yield of 4.45 ± 0.30 mgNH3 mgPd -1 h-1, almost tens of orders larger than for previously reported catalysts, and 100% reaction selectivity in neutral media. Pd-GDY exhibits almost no decreases in NH3 yield and Faradaic efficiency. Density functional theory calculations show that the reaction pathway prefers to perform at the (Pd, C1, C2) active area because of the strongly coupled (Pd, C1, C2), which elevates the selectivity via enhanced electron transfer. By adjusting the p-d coupling accurately, reduction of self-activated nitrogen is promoted by anchoring atom selection, and side effects are minimized.

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients.

Objective: Intellectual disability (ID) is one of the most common developmental disabilities. To identify the genetic etiology of IDs in Chongqing, we conducted a multistage study in Chinese Han patients. Methods: We collected the clinical and etiological data of 1665 ID patients, including 1,604 from the disabled children evaluation center and 61 from the pediatric rehabilitation unit. Routine genetic screening results were obtained, including karyotype and candidate gene analysis. Then 105 idiopathic cases with syndromic and severe ID/developmental delay (DD) were selected and tested by chromosomal microarray (CMA) and whole exome sequencing (WES) sequentially. The pathogenicity of the CNVs and SNVs were evaluated according to ACMG guidelines. Results: Molecular diagnosis was made by routine genetic screening in 216 patients, including 196 chromosomal syndromes. Among the 105 idiopathic patients, 49 patients with pathogenic/likely pathogenic CNVs and 21 patients with VUS were identified by CMA. Twenty-six pathogenic CNVs underlying well-known syndromic cases, such as Williams-Beuren syndrome, were confirmed by multiplex ligation-dependent probe amplification (MLPA). Nine novel mutations were identified by WES in thirty-fix CNV-negative ID cases. Conclusions: The study illustrated the genetic aberrations distribution of a large ID cohort in Chongqing. Compared with conventional or single methods, a tiered high-throughput diagnostic strategy was developed to greatly improve the diagnostic yields and extend the variation spectrum for idiopathic syndromic ID cases.

Consumers' attention on identification, nutritional compounds, and safety in heavy metals of Canadian sea cucumber in Chinese food market.

BACKGROUND: Based on the consumers' attention issues of sea cucumbers, we aimed to complete comprehensive information of commercial Canadian sea cucumbers (CCSC), which sprang up extensively in Chinese food market. RESULTS: CCSC were identified as Cucumaria frondosa and characterized based on the characteristics, nutritional compositions, and heavy metals. The abdomen and five internal tendons of Cucumaria frondosa were special orange. The average of soaking degree and water content, which consumers paid great attention to, was 2.8 ± 0.3 and 0.46 ± 0.09%, respectively. Proteins (56.4 ± 9.1%) and polysaccharides (12.2 ± 14.7%) were the principal nutrient component. In addition, there was a variety of free amino acids, in which arginine (70.1 ± 50.0 mg/100 g), glutamate (42.6 ± 23.9 mg/100 g), and alanine (32.2 ± 21.0 mg/100 g) were the main components. Phosphorus (P, 0.26 ± 0.05%), magnesium (Mg, 0.19 ± 0.07%), and kalium (K, 0.17 ± 0.08%) were the major mineral elements. Amount of heavy metal was within the safety limitation (5.5 ± 1.4 mg/kg). Furthermore, the active ingredients were positively correlated with size. CONCLUSION: The overall findings enriched the information of Cucumaria frondosa for consumers and suggested that the quality of Cucumaria frondosa was varied following commercial classification and size.

Immunomodulatory mechanism of a purified polysaccharide isolated from Isaria cicadae Miquel on RAW264.7 cells via activating TLR4-MAPK-NF-κB signaling pathway.

The immunomodulatory effect of a novel purified polysaccharide (JCH-1) isolated from Isaria cicadae Miquel had been confirmed to promote secretion of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) in our previous study. However, the immunomodulatory mechanism was still unclear. The purpose of this study was to investigate the immunomodulatory mechanism of JCH-1. Experimental data showed that JCH-1 could increase protein expression of toll-like receptor 4 (TLR4), promote the phosphorylation of mitogen-activated protein kinase (MAPK), as well as nuclear factor-kappa B (NF-κB) p65. Importantly, TLR4 inhibitor inhibited JCH-1-induced activation of MAPK-NF-κB signaling pathway, thus suppressed JCH-1-induced secretion of NO, TNF-α and IL-6. Collectively, these results indicated that JCH-1 actives RAW264.7 cells through TLR4-MAPK-NF-κB signaling pathway.

A highly selective and active metal-free catalyst for ammonia production.

We report a facile surface-induced method for the in situ growth of single-/few-layered crystalline fluorographdiyne film on the surface of carbon fibers (cFGDY). The crystallized structure of cFGDY was directly confirmed by the scanning/transmission electron microscopy (SEM/TEM), high-resolution TEM (HRTEM) and computer simulation, selected area electron diffraction (SAED), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. cFGDY showed a 9-fold stacking mode. Our results show that cFGDY is a metal-free electrocatalyst with unique structure and excellent performance for ammonia production from nitrogen and water efficiently at room temperature and ambient pressure, achieving a high NH3 production rate and Faraday efficiency in neutral conditions. This work provides an efficient catalyst system with determined chemical and electronic structures for highly selective and active nitrogen reduction, serving as a promising platform towards the development of novel metal-free catalysts.

Graphdiyne Interface Engineering: Highly Active and Selective Ammonia Synthesis.

A freestanding 3D graphdiyne-cobalt nitride (GDY/Co2 N) with a highly active and selective interface is fabricated for the electrochemical nitrogen reduction reaction (ECNRR). Density function theory calculations reveal that the interface-bonded GDY contributes an unique p-electronic character to optimally modify the Co-N compound surface bonding, which generates as-observed superior electronic activity for NRR catalysis at the interface region. Experimentally, at atmospheric pressure and room temperature, the electrocatalyst creates a new record of ammonia yield rate (Y NH 3 ) and Faradaic efficiency (FE) of 219.72 µg h-1 mgcat. -1 and 58.60 %, respectively, in acidic conditions, higher than reported electrocatalysts. Such a catalyst is promising to generate new concepts, new knowledge, and new phenomena in electrocatalytic research, driving rapid development in the field of electrocatalysis.

Methods of extraction, separation, purification, structural characterization for polysaccharides from aquatic animals and their major pharmacological activities.

The further development of fishery resources is a hotspot in the development of the fishery industry. However, how to develop aquatic animal resources deeply is a key point to be solved in the fishery industry. Over the past decades, numerous aquatic animals have gained great attention in the development and utilization of their bioactive molecules which are of therapeutic applications as nutraceuticals and pharmaceuticals. Recent research revealed that aquatic animals are composed of many vital moieties, such as polysaccharides and proteins, which provide health benefits beyond basic nutrition. In particular, aquatic animal polysaccharides are gaining worldwide popularity owing to their high content, ease of extraction, specific structure, few side effects, prominent therapeutic potential and incorporation in functional foods and dietary supplements. Thus, tremendous research on the isolation, identification and bioactivities of polysaccharides has been carried out. This review presents comprehensive viewpoints on extraction, separation, purification, structural characterization and bioactivity of various polysaccharides from aquatic animals, such as sea cucumber, abalone, oyster and mussels. In addition, this review profiled a brief knowledge on both current challenges and future scope in aquatic animal polysaccharides field. The review will be a direction of deep processing in fishery resources, which is a hotspot, but technical bottleneck. Furthermore, the review could be served as a useful reference material for further investigation, production and application of polysaccharides from aquatic animals in functional foods and therapeutic agents.

A novel case of global developmental delay syndrome with microdeletion at 10p14-p15.3 and microduplication at 18p11.31-p11.32.

To characterize the etiology underlying a novel case of global developmental delay syndrome (GDDS) identified in a female child, aged 3 years old. This syndrome is a common pediatric presentation estimated to affect 3.65% of children aged 3 to 17 years.The proband's detailed family history was used to infer a likely mode of inheritance for the GDDS. Genomic DNA samples collected from the proband and her parents were evaluated using conventional karyotyping, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization microarray (aCGH), and fluorescent in situ hybridization (FISH) analysis techniques.An analysis of the proband's family history suggested that she inherited the GDDS from her father. The conducted conventional karyotyping and MLPA methods failed to identify a causative defect for the GDDS; however, the aCGH analysis revealed both a 6.6-Mb deletion at p14-p15.3 of chromosome 10 (arr[hg19]; 100,026-6,710,183), and a 6.3-Mb duplication at p11.31-p11.32 of chromosome 18 (arr[hg19]; 136,226-6,406,733) in the proband. The conducted FISH analysis subsequently determined that these mutations resulted from a balanced translocation t(10;18)(p15.3; p11.32) carried by the proband's father. Finally, a bioinformatic analysis of the proband's mutations revealed ZMYND11 as a promising candidate causative gene for this case of GDDS.The present study demonstrates that the aCGH method can be used to effectively identify the location and approximate size of microdeletions and/or microduplications, but not balanced reciprocal translocations. The nonconventional analysis methods used in the present study may be applicable to other GDDS cases with elusive etiology, and likewise, ZMYND11 should be considered as a potential causative gene during the investigation of future GDDS cases.

Homozygosity mapping and whole exome sequencing reveal a novel ERCC8 mutation in a Chinese consanguineous family with unique cerebellar ataxia.

BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined. RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families. CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.