Evolution and Comprehensive Analysis of DNaseI Hypersensitive Sites in Regulatory Regions of Primate Brain-Related Genes

How the human brain differs from those of non-human primates is largely unknown and the complex drivers underlying such differences at the genomic level remain unclear. In this study, we selected 243 brain-related genes, based on Gene Ontology, and identified 184,113 DNaseI hypersensitive sites (DHSs) within their regulatory regions. To performed comprehensive evolutionary analyses, we set strict filtering criteria for alignment quality and filtered 39,132 DHSs for inclusion in the investigation and found that 2,397 (~6%) exhibited evidence of accelerated evolution (aceDHSs), which was a much higher proportion that DHSs genome-wide. Target genes predicted to be regulated by brain-aceDHSs were functionally enriched for brain development and exhibited differential expression between human and chimpanzee. Alignments indicated 61 potential human-specific transcription factor binding sites in brain-aceDHSs, including for CTCF, FOXH1, and FOXQ1. Furthermore, based on GWAS, Hi-C, and eQTL data, 16 GWAS SNPs, and 82 eQTL SNPs were in brain-aceDHSs that regulate genes related to brain development or disease. Among these brain-aceDHSs, we confirmed that one enhanced the expression of GPR133, using CRISPR-Cas9 and western blotting. The GPR133 gene is associated with glioblastoma, indicating that SNPs within DHSs could be related to brain disorders. These findings suggest that brain-related gene regulatory regions are under adaptive evolution and contribute to the differential expression profiles among primates, providing new insights into the genetic basis of brain phenotypes or disorders between humans and other primates

Predictive biomarkers for immune-related adverse events in cancer patients treated with immune-checkpoint inhibitors

Abstract Purpose The objective of this study was to identify potential predictors of immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitor therapy among serum indexes, case data, and liquid biopsy results. Methods We retrospectively analyzed 418 patients treated with anti-programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) inhibitors from January 2018 to May 2022 in our cancer center. We identified factors that correlated with the occurrence of irAEs and evaluated associations between irAEs and anti-PD-1/PD-L1 inhibitor responses. Results The incidence of irAEs was 42.1%, and pneumonitis (9.1%), thyroid toxicity (9.1%), cardiotoxicity (8.1%), and dermatologic toxicity (6.9%) were the four most common irAEs. Multivariate logistic analysis identified female sex, antibiotic use, higher post-treatment neutrophil-to-lymphocyte ratio (NLR), and higher baseline circulating tumor cell (CTC) level, as predictive biomarkers for the occurrence of irAEs. A lower baseline prognostic nutritional index (PNI), body mass index (BMI) ≥ 25 kg/m2, and higher post-treatment lactate dehydrogenase (LDH) level were predictive factors for more severe irAEs (higher severity grade). Patients without irAEs had better overall survival than those with irAEs. Specifically, pneumonitis and cardiotoxicity were found to be significant predictors of poor prognosis in the irAE subgroup with different organ-related irAEs. Low-dose steroid (dexamethasone 10 mg) treatment had no significant effect on outcomes. Conclusions Gender, antibiotic use, post-treatment NLR, and baseline CTC level are potential predictive biomarkers of irAEs, while baseline PNI, BMI, and post-treatment LDH may predict the severity of irAEs. The predictive effect of irAE occurrence on survival benefit may depend on the type of irAE

Safety and Efficacy of Tianfoshen Oral Liquid in Non-Small Cell Lung Cancer Patients as an Adjuvant Therapy

Ethnopharmacological Relevance. As an important Chinese herb injection, Tianfoshen (TFS) oral liquid is widely used in Chinese non-small cell lung cancer (NSCLC) patients. Aim of the Study. To evaluate the efficacy and safety of Tianfoshen (TFS) oral liquid plus chemotherapy in Chinese NSCLC patients with Qi and Yin deficiency syndrome, an observational study was conducted in Beijing Friendship Hospital between August 2012 and July 2016. Patients, enrolled in this study, were diagnosed with NSCLC and were treated with Cisplatin in combination with Paclitaxel/Navelbine/Gemcitabine/Docetaxel as a first-line treatment, or Pemetrexed for recurrent patients. The primary endpoint was the improvement of traditional Chinese medicine syndrome and objective response rate in patients. The secondary endpoint was the occurrence of drug-related adverse events. Results. A total of 108 patients were included in this study and underwent the safety and efficacy assessments. Compared to the baseline, the total scores of traditional Chinese medicine (TCM) syndrome after 3 or 8/9 weeks of TFS treatment were statistically significant (P<0.0001), and the clinical efficiency rate was 36.11% and 50.93%, respectively. The objective response rate (ORR) and disease control rate (DCR) of TFS group were slightly higher than those of without-TFS group, although the comparison was not statistically significant. The incidence of common adverse events related to TFS was 7.41% whereas the incidence of serious adverse events was 0.93%. Conclusions. As an adjuvant therapy of chemotherapy, TFS showed an acceptable tolerability profile in the clinical practice of Chinese NSCLC patients with Qi and Yin deficiency syndrome, but it seems to have no effect on the ORR and DCR

Integrated Treatment Technology of Storage-Mining Inclined Goaf under Expressway

An inclined goaf caused by storage mining is a serious risk to subgrades and pavements. In this paper, effective investigation and detection methods of goafs were discussed considering the project of the Urumqi East Ring Expressway crossing the existing goaf of Zhongxing no. 2 mine. Moreover, by theoretical analysis and a series of field comparative tests, reasonable grouting parameters and the treatment plan were obtained. By comparing the test results of the field and laboratory, the influence of groundwater on the effect of grouting was revealed to reduce the compressive strength of the consolidating objects of the slurry. The high-density resistivity method presented strong anti-interference ability and high accuracy in a depth range of less than 150 m in the investigation of the goaf. The results of the treatment showed that it is necessary to conduct research and analysis from multiple aspects to obtain the best treatment plan of a goaf and ensure the safety of a project

Response of a Sylvan Moss Species (<i>Didymodon validus</i> Limpr.) with a Narrow Distribution Range to Climate Change

Mosses are particularly susceptible to climate change owing to their close biological and ecological associations with climatic conditions. However, there is a limited understanding of the changes in distribution patterns of the moss species in forest ecosystems under climate change, especially in mosses with narrow ranges. Therefore, we reconstructed historical, simulated present, and predicted future potential distribution patterns of Didymodon validus, a narrow-range moss species in the forest ecosystem, using the MaxEnt model. The aim of this study was to explore its unique suitable habitat preference, the key environmental factors affecting its distribution, and the distributional changes of D. validus under climate change at a long spatial-time scale. Our findings indicate that the most suitable locations for D. validus are situated in high-altitude regions of southwestern China. Elevation and mean temperature in the wettest quarter were identified as key factors influencing D. validus distribution patterns. Our predictions showed that despite the dramatic climatic and spatial changes over a long period of time, the range of D. validus was not radically altered. From the Last Interglacial (LIG) to the future, the area of the highly suitable habitat of D. validus accounted for only 15.3%–16.4% of the total area, and there were weak dynamic differences in D. validus at different climate stages. Under the same climate scenarios, the area loss of suitable habitat is mainly concentrated in the northern and eastern parts of the current habitat, while it may increase in the southern and eastern margins. In future climate scenarios, the distribution core zone of suitable habitat will shift to the southwest for a short distance. Even under the conditions of future climate warming, this species may still exist both in the arid and humid regions of the QTP in China. In summary, D. validus showed cold and drought resistance. Our study provides important insights and support for understanding the impact of climate change on the distribution of D. validus, as well as its future distribution and protection strategies

GDF15 Repression Contributes to 5-Fluorouracil Resistance in Human Colon Cancer by Regulating Epithelial-Mesenchymal Transition and Apoptosis

Chemotherapy based on 5-fluorouracil (5-FU) is the standard approach for colon cancer treatment, and resistance to 5-FU is a significant obstacle in the clinical treatment of colon cancer. However, the mechanisms underlying 5-FU resistance in colon cancer cells remain largely unknown. This study aimed at determining whether 5-FU-resistant colon cancer cells undergo epithelial-mesenchymal transition (EMT) and apoptosis and the role of GDF15—a member of the transforming growth factor β/bone morphogenetic protein super family and a protein known to be involved in cancer progression—in the regulation of EMT and apoptosis of these cells, along with the underlying mechanisms. In vitro apoptosis detection assay, growth inhibition assay, transwell, and wound healing experiments revealed that 5-FU-resistant colon cancer cells possessed enhanced EMT and antiapoptotic ability. These cells also showed a stronger tendency to proliferate and metastasize in vivo. Quantitative reverse transcription-PCR and western blotting revealed that 5-FU-resistant colon cancer cells expressed lower levels of growth differentiation factor 15 (GDF15) than did 5-FU-sensitive colon cancer cells. Moreover, the transient GDF15 overexpression resensitized 5-FU-resistant colon cells to 5-FU. Collectively, these findings indicate the mechanism underlying the 5-FU resistance of colon cancer cells and provide new therapeutic targets for improving the prognosis of colon cancer patients

Baicalin circumvents anti-PD-1 resistance by regulating the gut microbiota metabolite short-chain fatty acids

Baicalin is a small molecule medication used to treat hepatitis. Our research group discovered that administering baicalin orally to mice following fecal microbiota transplantation from patients resistant to ICIs supported anti-PD-1 activity. However, the precise mechanisms behind this effect are presently unknown. In this present study, ATB-treated C57BL/6 J mice received FMT from patients with advanced NSCLC amenable to αPD-1. Additionally, subcutaneous LLC cells were injected into the mice. Baicalin oral gavage and αPD-1 injection were administered to the mice on days 3 and 9 after tumour inoculation. 16 S rRNA, metabolomics, and flow cytometry were utilized to clarify the mechanisms of baicalin's relief of immunosuppression. The results indicated that oral administration of baicalin enriched bacteria such as Akkermansia and Clostridia_UCG-014, resulted in an increase in SCFAs, which improved the ratio of PD-1+ (CD8+ T cell/Treg) and promoted the levels of IFN-γ+ CD8+ T cells and TNF-α+ CD8+ T cells within the tumour microenvironment. In conclusion, baicalin regulates the metabolites of the gut microbiota to improve the PD-1+ (CD8+ T cell/Treg) balance and circumvent anti-PD-1 resistance. This is achieved through the regulation of short-chain fatty acids