PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

High Net Information Density DNA Data Storage by the MOPE Encoding Algorithm.

DNA has recently been recognized as an attractive storage medium due to its high reliability, capacity, and durability. However, encoding algorithms that simply map binary data to DNA sequences have the disadvantages of low net information density and high synthesis cost. Therefore, this paper proposes an efficient, feasible, and highly robust encoding algorithm called MOPE (Modified Barnacles Mating Optimizer and Payload Encoding). The Modified Barnacles Mating Optimizer (MBMO) algorithm is used to construct the non-payload coding set, and the Payload Encoding (PE) algorithm is used to encode the payload. The results show that the lower bound of the non-payload coding set constructed by the MBMO algorithm is 3%-18% higher than the optimal result of previous work, and theoretical analysis shows that the designed PE algorithm has a net information density of 1.90 bits/nt, which is close to the ideal information capacity of 2 bits per nucleotide. The proposed MOPE encoding algorithm with high net information density and satisfying constraints can not only effectively reduce the cost of DNA synthesis and sequencing but also reduce the occurrence of errors during DNA storage.

[Research Progress of Immune Checkpoint TIGIT in Lung Cancer Immunotherapy].

T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a newly discovered immune checkpoint molecule, mainly expressed on the surface of T cells and natural killer (NK) cells. By binding to cluster of differentiation 155 (CD155) and other ligands, it inhibits T cell and NK cell-mediated immune responses and affects the tumor microenvironment. Multiple preclinical studies have demonstrated that the TIGIT/CD155 pathway plays a role in a variety of solid and hematological tumors. Clinical trials investigating TIGIT inhibitors alone or in combination with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors for lung cancer are currently underway.
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[Two Cases of TKI-resistant Small Cell Lung Cancer Transformation 
in Advanced Adenocarcinoma and Literature Review].

Treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can achieve good disease control, but it will inevitably produce drug resistance. About 3%-10% of the resistance mechanism is small cell transformation. Two cases of stage IV lung adenocarcinoma with EGFR mutation were reported and the disease was controlled after EGFR-TKIs treatment. In case 1, progression-free survival (PFS) before small cell carcinoma transformation was 16 months, and in case 2, PFS before small cell carcinoma transformation was 24 months. Subsequent biopsy after disease progression indicated a shift to small cell lung cancer. Case 1 PFS after small cell carcinoma transformation was 6 months, and case 2 PFS after small cell carcinoma transformation was 8 months, and overall survival (OS) was 36 months, which significantly prolonged the patient's survival. At the same time, the literature of such drug resistance mutations was reviewed. For patients with advanced NSCLC with sensitive mutations, it is necessary to conduct secondary histopathological tests after TKIs treatment resistance, and select subsequent treatment according to different resistance mechanisms for the whole course of disease management.
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Enhancing Physical and Thermodynamic Properties of DNA Storage Sets With End-Constraint.

With the explosion of data, DNA is considered as an ideal carrier for storage due to its high storage density. However, low-quality DNA sets hamper the widespread use of DNA storage. This work proposes a new method to design high-quality DNA storage sets. Firstly, random switch and double-weight offspring strategies are introduced in Double-strategy Black Widow Optimization Algorithm (DBWO). Experimental results of 26 benchmark functions show that the exploration and exploitation abilities of DBWO are greatly improved from previous work. Secondly, DBWO is applied in designing DNA storage sets, and compared with previous work, the lower bounds of storage sets are boosted by 9%-37%. Finally, to improve the poor stabilities of sequences, the End-constraint is proposed in designing DNA storage sets. By measuring the number of hairpin structures, melting temperature, and minimum free energy, it is evaluated that with our innovative constraint, DBWO can construct not only a larger number of storage sets, but also enhance physical and thermodynamic properties of DNA storage sets.

Downregulation of LHPP Expression Associated with AFP Acts as a Good Prognostic Factor in Human Hepatocellular Carcinoma.

BACKGROUND: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) serves as a tumor suppressor in hepatocellular carcinoma (HCC), but the correlation between the expression of LHPP and the clinical parameters of oncogenic progression is still not well defined. This study is to reveal the correlation between the expression of LHPP in HCC and their clinical parameters. METHODS: Immunohistochemical analysis was used to assess the correlation between the expression of LHPP and the clinical parameters of HCC. Expressions of LHPP in HCC tissues and cultured HCC cells were detected by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). LHPP, gamma-glutamyl transferase (GGT), and α-fetoprotein (AFP) expression levels in blood or HCC tissues were detected by enzyme-linked immunosorbent assay (ELISA). The Spearman rank correlation coefficient was used to evaluate the correlation of the expression of LHPP and the clinical index of HCC. Correlation of survival and expression of LHPP were analyzed using the Kaplan-Meier method and the log-rank test. RESULTS: Expressions of LHPP in HCC tissues were significantly downregulated than their paired adjacent normal tissues. A significant positive correlation was found between the cytoplasm and nuclear expression of LHPP in both HCC and their paired adjacent normal tissues. The expression of LHPP negatively correlated with the levels of GGT in the cytoplasm of adjacent tissues and with the AFP level in the nucleus of HCC cells. Relative levels of LHPP in HCC tissues were markedly lower than those of the paired adjacent normal tissues. Relative levels of LHPP in LO-2 cells were higher than those of HepG2, BEL-7404, and SMMC-7721 cell lines. The overall survival and DSF survival of patients with the high expression of LHPP were much higher than those with the low expression of LHPP in paired adjacent normal tissue. CONCLUSIONS: LHPP is associated with the AFP level and acts as a good prognostic factor in HCC.

A systematic approach to decode the mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC).

Cornus Officinalis (Cornus), the dried pulp of mature Cornus, is used to treat liver diseases. However, the pharmacological mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC) has not been systematically studied. The chemical compounds and the bioactive chemical compounds of Cornus were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Cards database was used to explore the targets in liver cancer pathogenesis. The disease-drug Venn diagram was constructed using the VENN 2.1 and the STRING database was used to analyze protein-protein Interaction Network (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R package. Molecular docking was performed using Discovery Studio were assessed using Pymol and Discovery Studio 2016. Cell survival of BEL-7404 cells treated by Hydroxygenkwanin (HGK) were valued through CCK-8 assay. Expressions of caspase-3 and cleaved PARP was detected through Western blot. Pharmacological network diagrams of the Cornus compound-target network and HCC-related target network were successfully constructed. A total of 20 active compounds, 1841 predicted biological targets of Cornus, and 7100 HCC-related targets were identified. 37 target genes between Cornus and HCC were screened trough the network pharmacology. Molecular docking studies suggested that HGK has the highest affinity with caspase-3. HGK could induce apoptosis of HCC cells and significantly activate the caspase-3 protease activity in BEL-7404. This study systematically elaborated the mechanism of Cornus in the treatment of HCC and provided a new perspective to exploit Antineoplastic from Cornus.

A new discovery of STAT4 single nucleotide polymorphisms associated with hepatocellular carcinoma risk in Chinese Han population: a case-control study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common fatal malignant tumor worldwide. Signal transducer and activator of transcription 4 (STAT4) is HCC susceptibility gene identified by genome-wide association study. The purpose of the present study was to determine the association between four candidate single nucleotide polymorphisms (SNPs) in STAT4 genes and HCC risk in Chinese Han population. METHODS: A case-control study was conducted to assess the association between STAT4 SNPs and HCC risk in 1011 Chinese Han population. Agena MassARRAY was used to genotype SNPs. The association between SNPs and HCC susceptibility under different genetic models was evaluated by logistic regression analysis. Multifactorial dimension reduction (MDR) analyzed the interaction of 'SNP-SNP' in HCC risk. The difference of clinical characteristics between different genotypes was completed by ANOVA. RESULTS: The results showed that STAT4 rs11889341 was significantly associated with HCC risk under multiple genetic models (homozygote: odds ratio (OR) = 0.60, P=0.033; recessive: OR = 0.63, P=0.028; log-additive: OR = 0.83, P=0.032). The results of subgroup analysis showed that STAT4 rs11889341 is significantly associated with HCC risk with participants who were >55 years, male or smoking. Both STAT4 rs7574865 and rs10174238 were significantly associated with HCC risk among participants who were >55 years, smoking or drinking. STAT4 haplotype (Trs11889341Trs7574865) could reduce the risk of HCC. In addition, rs11889341 and rs7574865 were significantly associated with the level of serum ferritin (SF). CONCLUSION: STAT4 rs11889341, rs7574865 or rs10174238 is potentially associated with HCC risk in Chinese Han population. In particular, rs11889341 showed outstanding association with HCC risk.

CLGBO: An Algorithm for Constructing Highly Robust Coding Sets for DNA Storage.

In the era of big data, new storage media are urgently needed because the storage capacity for global data cannot meet the exponential growth of information. Deoxyribonucleic acid (DNA) storage, where primer and address sequences play a crucial role, is one of the most promising storage media because of its high density, large capacity and durability. In this study, we describe an enhanced gradient-based optimizer that includes the Cauchy and Levy mutation strategy (CLGBO) to construct DNA coding sets, which are used as primer and address libraries. Our experimental results show that the lower bounds of DNA storage coding sets obtained using the CLGBO algorithm are increased by 4.3-13.5% compared with previous work. The non-adjacent subsequence constraint was introduced to reduce the error rate in the storage process. This helps to resolve the problem that arises when consecutive repetitive subsequences in the sequence cause errors in DNA storage. We made use of the CLGBO algorithm and the non-adjacent subsequence constraint to construct larger and more highly robust coding sets.

ADCY2 rs10059539 C>T polymorphism confers a decreased risk of hepatocellular carcinoma in Chinese Han women.

OBJECTIVE: Hepatocellular carcinoma (HCC) poses a serious threat to human health. ADCY2 gene polymorphisms may be related to HCC susceptibility. Therefore, we investigated whether ADCY2 gene polymorphisms are correlated to the risk of HCC in a Chinese Han population. METHODS: In a case-control study, we examined the associations between single nucleotide polymorphisms (SNPs) in ADCY2 and HCC risk. In 434 HCC cases and 442 healthy controls, we used the Agena MassARRAY platform to select and genotype four tag SNPs in ADCY2. We used logistic regression after adjusting for age and sex to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The results showed that ADCY2 rs10059539 polymorphism was associated with a reduced susceptibility to HCC in women under the dominant model (TC/TT vs. CC; OR = 0.32; 95% CI = 0.13-0.83; P = 0.018) and the log-additive model (OR = 0.32; 95% CI = 0.13-0.83; P = 0.018). CONCLUSIONS: Our results support the hypothesis that ADCY2 gene polymorphisms influence the genetic susceptibility to HCC.

Minimum Free Energy Coding for DNA Storage.

With the development of information technology, huge amounts of data are produced at the same time. How to store data efficiently and at low cost has become an urgent problem. DNA is a high-density and persistent medium, making DNA storage a viable solution. In a DNA data storage system, the first consideration is how to encode the data effectively into code words. However, DNA strands are prone to non-specific hybridization during the hybridization reaction process and are prone to errors during synthesis and sequencing. In order to reduce the error rate, a thermodynamic minimum free energy (MFE) constraint is proposed and applied to the construction of coding sets for DNA storage. The Brownian multi-verse optimizer (BMVO) algorithm, based on the Multi-verse optimizer (MVO) algorithm, incorporates the idea of Brownian motion and Nelder-Mead method, and it is used to design a better DNA storage coding set. In addition, compared with previous works, the coding set has been increasing by 4%-50% in size and has better thermodynamic properties. With the improvement of the quality of the DNA coding set, the accuracy of reading and writing and the robustness of the DNA storage system are also enhanced.

Lung squamous cell carcinoma with rare epidermal growth factor receptor mutation G719X: a case report and literature review.

Asians who develop non-small cell lung cancer (NSCLC) have a chance of approximately 50% of harboring the epidermal growth factor receptor (EGFR) mutation. The G719X mutation in EGFR has 3 subtypes (i.e., G719A, G719C, or G719S), all of them being classified as uncommon EGFR mutations. The EGFR mutation G719X is most often associated with lung adenocarcinoma. Conversely, its occurrence in lung squamous cell carcinoma is rare. Its response to tyrosine kinase inhibitor (TKI) treatment remains unknown. A 50-year-old Asian male with no smoking history was admitted to our hospital (Affiliated Hospital of Qingdao University) with an irritating dry cough and 1 month of progressive dyspnea. The patient was diagnosed with lung squamous cell carcinoma (cT4N3M0, stage IIIC). Lung biopsy revealed the presence of EFGR G719X mutation. The patient received a tracheobronchial stent, targeted therapy, chemotherapy, seed implantation and radiotherapy, and survived for 25.4 months following diagnosis. It is crucial that gene mutation analysis is performed in non-smoking male squamous cell carcinoma patients. Compared to lung adenocarcinoma patients with rare G719X mutation, this lung squamous cell carcinoma patient with G719X-mutant tumor had a higher sensitivity to 2nd-generation EGFR-TKI treatment, but similar progression-free survival. Importantly, the patient clearly benefited from the used comprehensive treatment plan. This article seeks to shed light on the treatment of lung squamous cell carcinoma patients with the uncommon EGFR G719X mutation.

Exploring the Potential Mechanism of Guchang Zhixie Wan for Treating Ulcerative Colitis by Comprehensive Network Pharmacological Approaches and Molecular Docking Validation as Well as Cell Experiments.

Guchang Zhixie Wan (GZW) is a commonly used Chinese medicine for the treatment of ulcerative colitis (UC). This research explored the potential pharmacological mechanism of GZW in UC. The active ingredients, potential targets, and UC-related genes of GZW were retrieved from public databases. The pharmacological mechanisms including key components, potential targets and signal pathways were determined through bioinformatics analysis. The results of this study were verified through virtual molecular docking and cell experiments. Network analysis revealed that 26 active GZW compounds and 148 potential GZW target proteins were associated with UC. Quercetin, kaempferol and ß-sitosterol were identified as the core active ingredients of GZW. IFNG, IL-1A, IL-1B, JUN, RELA, and STAT1 were indicated as key targets of GZW. These key targets have a strong affinity for quercetin, kaempferol, and ß-sitosterol. GO and KEGG enrichment analysis showed that GZW target proteins are highly enriched in inflammatory, immune, and oxidative stress-related pathways. This study confirmed the therapeutic effect and revealed potential molecular mechanism of GZW on UC. And the protective effects of GZW on inflammatory bowel disease pathway were also revealed through STAT3/NF-κB/IL-6 pathway. The findings of this study enhanced our understanding of GZW in the treatment of UC and provided a feasible method for discovering potential drugs from traditional Chinese medicine formulations.

Post-marketing Re-evaluation of Tongxiening Granules () in Treatment of Diarrhea-Predominant Irritable Bowel Syndrome: A Multi-center, Randomized, Double-Blind, Double-Dummy and Positive Control Trial.

OBJECTIVE: To evaluate the efficacy and safety of Tongxiening Granules (, TXNG) in the treatment of irritable bowel syndrome with predominant diarrhea (IBS-D). METHODS: A randomized, double-blind, double-dummy, and positive parallel controlled clinical trial was conducted from October 2014 to March 2016. Totally 342 patients from 13 clinical centers were enrolled and randomly assigned (at the ratio of 1:1) to a treatment group (171 cases) and a control group (171 cases) by a random coding table. The patients in the treatment group were administered orally with TXNG (5 g per time) combined with pinaverium bromide Tablet simulator (50 mg per time), 3 times per day. The patients in the control group were given TXNG simulator (5 g per time) combined with pinaverium bromide Tablets (50 mg per time), 3 times per day. The treatment course lasted for 6 weeks. The improvement of Irritable Bowel Syndrome Symptom Severity Score (IBS-SSS) was used to evaluate the primary outcome. Secondary outcomes included adequate relief (AR) rate, Irritable Bowel Syndrome-Quality of Life Questionnaire (IBS-QOL), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and the recurrence rate at follow-ups. Safety indices including the adverse events (AEs) and related laboratory tests were evaluated. RESULTS: Primary outcome: IBS-SSS at baseline, weeks 2, 4, 6 showed no statistical significance in both full analysis set (FAS) and per protocol set (PPS, P>0.05). After 6 weeks of treatment, the total effective rate of IBS-SSS scores in the treatment group (147/171,86.0%) was higher than the control group (143/171, 83.6%) by FAS (P>0.05). In regard to secondary outcomes, after 6-week treatment, there was no significant difference in AR rate, total score of IBS-QOL, improvement of HAMD and HAMA total scores between the two groups (P>0.05). The recurrence rate at 8-week follow-up was 12.35% (10/18) in treatment group and 15.79% (12/76) in control group, respectively (P>0.05). A total of 21 AEs occurred in 15 cases, of which 11 occurred in 8 cases in the treatment group and 10 AEs in 7 cases in the control group. The incidence of AEs had no statistical significance between the two goups (P>0.05). CONCLUSION: Tongxiening Granules could relieve the symptoms of patients with IBS-D and the treatment effect was comparable to pinaverium bromide. (No. ChiCTR-IPR-15006415).

The effects and mechanism of peiminine-induced apoptosis in human hepatocellular carcinoma HepG2 cells.

Peiminine is a compound isolated from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), which has demonstrated antitumor activities. But its precise molecular mechanism underlying antitumor activity remain elusive. In this study, peiminine-induced apoptosis towards human hepatocellular carcinoma and its molecular mechanism were investigated. MTT assay was employed to assess anticancer effects of peiminine upon Hela, HepG2, SW480 and MCF-7 cell lines. Nuclear staining and flow cytometry were carried out to detect apoptosis induced by peiminine. Mitochondrial membrane potential evaluation and Western blot analysis were performed to investigate the mechanism of peiminine-induced apoptosis. The results showed peiminine reduced the viability of HepG2 cells in a time- and dose-dependent manner and had an IC50 of 4.58 µg/mL at 24h. Peiminine significantly increased the percentage of apoptotic cells and the mitochondrial membrane potential dose-dependently in HepG2 cells. The results of Western blotting indicated the expressions of Bcl-2, procaspase-3, procaspase-8, procaspase-9, and PARP decreased in HepG2 cells treated with peiminine, while the expressions of Bax, caspase-3, caspase-8, caspase-9, and cleaved PARP1 increased. The result suggests that peiminine can induce apoptosis in human hepatocellular carcinoma HepG2 cells through both extrinsic and intrinsic apoptotic pathways.

QingBai decoction regulates intestinal permeability of dextran sulphate sodium-induced colitis through the modulation of notch and NF-κB signalling.

OBJECTIVE: Chinese Herb QingBai decoction (QBD) has been approved affective in the treatment of IBD patients in clinic. However, the underlying mechanism remains unknown. We aim to investigate the effect of QBD on the mouse model of ulcerative colitis and its possible mechanism. METHODS: C57/bL mice were given 5% DSS to induce colitis and were divided as QBD and mesalazine group. Weight, faeces and mental status were recorded each day and the histopathological changes (goblet cells etc) of the colon were observed after sacrificed. Fluorescein isothiocyanate-dextran 4000 was measured to reflect the intestinal mucosal permeability. In addition, cell junction-related proteins and possible signal pathways were investigated. RESULTS: QingBai decoction could significantly alleviate the inflammation and the protection effect of colitis is comparable as those in mesalazine enema group. It was found that the permeability reduced significantly with QBD treatment vs the control group, while no significant difference between the mesalazine and QBD groups. QBD treatment could upregulate the expression of tight junction complex（ZO-1, claudin-1 and occludin）and muc-2 expression. It significantly reduced the production and secretion of serials proinflammatory cytokines (IL-1ß, IL-6, Kc and TNF-α) compared with the control group. Meanwhile, NF-κB and Notch pathways were regulated. CONCLUSION: QingBai decoction can effectively alleviate intestinal inflammation and mucosal barrier function in colitis mice, and the mechanism may be related to the inhibition of inflammatory cascade as well as enhanced mucus layer barrier and mechanical barrier function by NF-κB and Notch signalling.