Cell type-specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases.

Necroptosis is generally considered as an inflammatory cell death form. The core regulators of necroptotic signaling are receptor-interacting serine-threonine protein kinases 1 (RIPK1) and RIPK3, and the executioner, mixed lineage kinase domain-like pseudokinase (MLKL). Evidence demonstrates that necroptosis contributes profoundly to inflammatory respiratory diseases that are common public health problem. Necroptosis occurs in nearly all pulmonary cell types in the settings of inflammatory respiratory diseases. The influence of necroptosis on cells varies depending upon the type of cells, tissues, organs, etc., which is an important factor to consider. Thus, in this review, we briefly summarize the current state of knowledge regarding the biology of necroptosis, and focus on the key molecular mechanisms that define the necroptosis status of specific cell types in inflammatory respiratory diseases. We also discuss the clinical potential of small molecular inhibitors of necroptosis in treating inflammatory respiratory diseases, and describe the pathological processes that engage cross talk between necroptosis and other cell death pathways in the context of respiratory inflammation. The rapid advancement of single-cell technologies will help understand the key mechanisms underlying cell type-specific necroptosis that are critical to effectively treat pathogenic lung infections and inflammatory respiratory diseases.

Annealing-Tunable Charge Density Wave in the Magnetic Kagome Material FeGe.

The unprecedented phenomenon that a charge density wave (CDW) emerges inside the antiferromagnetic (AFM) phase indicates an unusual CDW mechanism associated with magnetism in FeGe. Here, we demonstrate that both the CDW and magnetism of FeGe can be effectively tuned through postgrowth annealing treatments. Instead of the short-range CDW reported earlier, a long-range CDW order is realized below 110 K in single crystals annealed at 320 °C for over 48 h. The CDW and AFM transition temperatures appear to be inversely correlated with each other. The onset of the CDW phase significantly reduces the critical field of the spin-flop transition, whereas the CDW transition remains stable against minor variations in magnetic orders such as annealing-induced magnetic clusters and spin-canting transitions. Single-crystal x-ray diffraction measurements reveal substantial disorder on the Ge1 site, which is characterized by displacement of the Ge1 atom from the Fe_{3}Ge layer along the c axis and can be reversibly modified by the annealing process. The observed annealing-tunable CDW and magnetic orders can be well understood in terms of disorder on the Ge1 site. Our study provides a vital starting point for the exploration of the unconventional CDW mechanism in FeGe and of kagome materials in general.

[Clinical Application of Microwave Ablation in Potentially Resectable Colorectal Cancer With Simultaneously Multiple Liver Metastases].

Objective To analyze the clinical efficacy of microwave ablation in the colorectal cancer with simultaneously multiple liver metastases that was initially evaluated as potentially resectable. Methods The patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases treated in the Department of General Surgery of the First Affiliated Hospital of Hebei North University,the Center of Minimally Invasive Therapy in Oncology of Traditional Chinese and Western Medicine in Dongzhimen Hospital of Beijing University of Chinese Medicine,and the Second Department of General Surgery in the Fourth Hospital of Hebei Medical University from October 1,2018 to October 1,2020 were selected in this study.The general data,pathological features,treatment methods,and clinical efficacy of the patients were collected.According to the treatment methods,the patients were assigned into a surgical resection group(conversion therapy+laparoscopic primary resection+hepatectomy)and a microwave ablation group(conversion therapy+laparoscopic primary resection+microwave ablation).The surgical indicators(operation duration,time to first postoperative anal exhaust,hospital stay,etc.)and postoperative complications(anastomotic stenosis,anastomotic hemorrhage,incision infection,etc.)were compared between the two groups.The survival period was followed up,including the overall survival period and disease-free survival period,and the survival curves were drawn to analyze the clinical efficacy of the two treatment regimens. Results A total of 198 patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases were included in this study.Sixty-six patients were cured by neoadjuvant chemotherapy(FOLFOX or FOLFIRI),including 30 patients in the surgical resection group and 36 patients in the microwave ablation group(with 57 tumors ablated).After the first ablation,54(94.74%)tumors achieved complete ablation,and all of them reached no evidence of disease status after re-ablation.The microwave ablation group had shorter operation duration,less intraoperative blood loss,shorter time to first postoperative anal exhaust,shorter time of taking a liquid diet,shorter hospital stay,and lower hospitalization cost than the surgical resection group(all P<0.001).In addition,the microwave ablation group had lower visual analogue scale score(P<0.001)than the surgical resection group.The incidences of complications such as incision infection(P=0.740),anastomotic fistula(P=1.000),and anastomotic stenosis(P=1.000),the overall survival period(P=0.191),and the disease-free survival period(P=0.934)showed no significant differences between the two groups. Conclusions For patients with colorectal cancer with simultaneous multiple liver metastases initially assessed as potentially resectable,laparoscopic primary resection+surgical resection/microwave ablation after conversion therapy was safe,effective,and had similar survival outcomes.Microwave ablation outperformed surgical resection in postoperative recovery,economy,and tolerability,being worthy of clinical promotion.

[Clinical Comparison of the Efficacy of Systemic Thrombolysis,Catheter-Directed Thrombolysis,and AngioJet Percutaneous Mechanical Thrombectomy in Acute Lower Extremity Deep Venous Thrombosis].

Objective To compare the clinical effects of three treatment methods including systemic thrombolysis(ST),catheter-directed thrombolysis(CDT),and AngioJet percutaneous mechanical thrombectomy(PMT)in acute lower extremity deep venous thrombosis(LEDVT). Methods The data of 82 patients diagnosed with LEDVT in the Department of Vascular and Gland Surgery of the First Affiliated Hospital of Hebei North University from January 2017 to December 2020 were collected.The patients were assigned into a ST group(n=50),a CDT group(n=16),and a PMT group(n=16)according to different treatment methods.The efficacy and safety were compared among the three groups. Results Compared with that before treatment,the circumferential diameter difference of both lower limbs on days 1,2,and 3 of treatment in the ST,CDT,and PMT groups reduced(all P<0.001).The PMT group showed smaller circumferential diameter difference of lower limbs on days 1,2,and 3 of treatment than the ST group(all P<0.001)and smaller circumferential diameter difference of the lower patellar margin on day 1 of treatment than the CDT group(P<0.001).The PMT group showed higher diminution rate for swelling of the affected limb at the upper and lower edges of the patella than the ST group(P<0.001)and higher diminution rate for swelling at the upper edge of the patella than the CDT group(P=0.026).The incidence of complications after treatment showed no significant differences among the three groups(all P>0.05).The median of hospital stay in the PMT group was shorter than that in the ST and CDT groups(P=0.002,P=0.001).The PMT group had higher thrombus clearance rate than the ST group(P=0.002)and no significant difference in the thrombus clearance rate from the CDT group(P=0.361).The vascular recanalization rates in the PMT(all P<0.001)and CDT(P<0.001,P=0.002,P=0.009)groups 3,6,and 12 months after treatment were higher than those in ST group,and there were no significant differences between PMT and CDT groups(P=0.341,P=0.210,P=0.341). Conclusions ST,CDT,and PMT demonstrated significant efficacy in the treatment of LEDVT,and PMT was superior to ST and CDT in terms of circumferential diameter difference of the lower limbs,diminution rate for swelling of the affected limb,thrombus clearance rate,length of hospital stay,and long-term vascular recanalization.There was no obvious difference in safety among the three therapies.

The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients.

BACKGROUND: Cell division control protein 42 (CDC42) is involved in colorectal cancer (CRC) progression by modulating CD8+ T cell activation, immune escape, and direct oncogenetic biological processes. This study aimed to explore the correlation of blood CDC42 with disease risk, comorbidities, disease features, tumor markers, and prognosis among CRC patients. METHODS: CDC42 in peripheral blood mononuclear cells was detected by reverse transcription-quantitative polymerase chain reaction from 250 resectable CRC patients and 50 healthy controls (HCs). CDC42 was divided by quartiles, as well as high and low expressions in CRC patients for correlation and survival analysis. RESULTS: CDC42 was elevated in CRC patients vs. HCs (p < 0.001), which had a good ability to distinguish CRC patients from HCs with the area under the curve (95% confidence interval) of 0.889 (0.841-0.937). In CRC patients, CDC42 was not associated with demographics or comorbidities (all p > 0.05), while its higher quartile was linked to increased T stage (p < 0.001), N stage (p = 0.009), TNM stage (p < 0.001), abnormal carcinoembryonic antigen (p = 0.043), and adjuvant chemotherapy administration (p = 0.002). Higher CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p < 0.001) were related to worse disease-free survival (DFS); meanwhile, elevated CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p = 0.001) were also linked to poor overall survival (OS). Multivariate Cox's regression analysis presented that CDC42 quartile 3 and 4 (vs. quartile 1) independently predicted declined DFS and OS (all p < 0.05). CONCLUSION: Circulating CDC42 relates to higher disease risk, T, N, and TNM stage, abnormal tumor marker, and poor prognosis among CRC patients.

Suppression of the CD28/B7 pathway reduces the occurrence and development of myasthenia gravis and cytokine levels.

BACKGROUND: Myasthenia gravis (MG) is an antibody-mediated, autoimmune neuromuscular disease. Reports have indicated that the CD28/B7 ligand interactions play a crucial role during primary immune responses. Hence, the aim of the present study was to investigate the possible effects of the CD28/B7 pathway on the occurrence and development of MG and its associated cytokine factors. METHODS: An experimental autoimmune myasthenia gravis (EAMG) was initially established by immunization of Lewis rats with acetylcholine receptor (AChR) α97-116 peptide. Then the rats were treated with dexamethasone and CTLA4-Ig (used for inhibiting the CD28/B7 pathway). Serum levels of AChR IgG and AChR IgG2b were then detected using ELISA. The clinical features, muscle contraction function, AChR content, expression of CD28, CTLA4, B7.1 and B7.2 in mononuclear cells of peripheral blood and the secretion of cytokines (INF-γ, IL-2, IL-10 and IL-12) in serum of rats were measured. Finally, lymphocyte proliferation upon CTLA4 IgG treatment was examined in vitro. RESULTS: Inhibition of the CD28/B7 pathway and dexamethasone were found to significantly improve clinical symptoms of EAMG rats, reduce serum levels of AChR IgG, AChR IgG2b, INF-γ, IL-2, IL-10 and IL-12, the expression of CD28, CTLA4, B7.1 and B7.2 in mononuclear cells of peripheral blood, and enhance muscle contraction function and AChR content in the muscle in vivo. Meanwhile, CTLA4 IgG could abolish the increased lymphocyte proliferation following AChR stimulation in vitro. CONCLUSION: Overall, the suppression of the CD28/B7 pathway by CTLA4-Ig can have the potential to retard the occurrence and development of MG.

[Relationship between Expression of Runt-related Transcription Factor 3 and Enhancer of zeste Homolog 2 Proteins and Sensitivity to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer].

Objective To investigate the expression and correlation of Runt-related transcription factor 3(RUNX3)and enhancer of zeste homolog 2(EZH2)in rectal cancer,and to reveal the relationship between the expression of RUNX3 and EZH2 and the sensitivity of XELOX regimen to neoadjuvant chemotherapy in locally advanced rectal cancer patients. Methods The carcinoma and paracancerous tissues of 31 patients with rectal adenocarcinoma and no preoperative antitumor therapy were selected as cancer group and paracancer group,respectively.The relative mRNA levels of RUNX3 and EZH2 in the two groups were measured by real-time quantitative reverse transcription-polymerase chain reaction,and the protein levels were determined by immunohistochemical assay.The expression of RUNX3 and EZH2 was compared between cancer tissue and paracancerous tissue.The pre-treatment wax blocks of 26 patients with locally advanced rectal cancer who received 3 cycles of XELOX regimen as neoadjuvant chemotherapy before surgery were selected as the pre-neoadjuvant therapy group,and the postoperative pathological wax blocks were selected as the post-neoadjuvant treatment group.Tumor regression grade(TRG)was determined to evaluate the efficacy of neoadjuvant therapy.Immunohistochemical assay was used to detect the protein levels of RUNX3 and EZH2 in the two groups,and then the relationship between the expression patterns of the two proteins and the efficacy of neoadjuvant chemotherapy was analyzed. Results Compared with paracancerous tissue,the cancer tissue showed down-regulated mRNA level and reduced positive protein expression rate of RUNX3,while up-regulated mRNA level(P=0.001)and increased positive protein expression rate of EZH2(P=0.022).The mRNA levels of RUNX3 and EZH2 in the cancer group were negatively correlated(r=-0.599,P=0.000).Twelve patients who received neoadjuvant chemotherapy reached TRG0-TRG2,and the overall effective rate of neoadjuvant chemotherapy was 46.15%(12/26).Compared with pre-neoadjuvant therapy group,the post-neoadjuvant therapy group had increased positive expression rate of RUNX3 protein(P=0.163)and decreased positive expression rate of EZH2 protein(P=0.095).In the pre-neoadjuvant therapy group,the effective rate of neoadjuvant chemotherapy was 75.00%(9/12)in patients with positive RUNX3 expression,77.78%(7/9)in patients with negative EZH2 expression,and 100%(7/7)in patients with positive expression of RUNX3 and negative expression of EZH2.Multivariate Logistic regression showed that the expression of RUNX3 protein was the factor influencing the efficacy of neoadjuvant chemotherapy. Conclusions The positive expression rate of RUNX3 in cancer tissue was lower than that in paracancerous tissue,while that of EZH2 showed the opposite trend.Neoadjuvant chemotherapy may affect the expression of RUNX3 and EZH2 in rectal cancer.The patients with high RUNX3 expression and low EZH2 expression in locally advanced rectal cancer were more sensitive to neoadjuvant chemotherapy with XELOX regimen.

[Expression of Runt-related Transcription Factor 3 in Human Colon Cancer Cell Line HCT-116 Resistant to 5-Fluorouracil and the Mechanism of Drug Resistance].

Objective To establish a human colon cancer cell line HCT-116/5-FU resistant to 5-fluorouracil(5-FU)and explore the relationship between runt-related transcription factor 3(RUNX3)and drug resistance of colorectal cancer.Methods The human colon cancer cell line HCT-116/5-FU with resistance to 5-FU was established by low concentration gradient increment combined with high-dose intermittent shock.CCK-8 method was used to determine the half maximal inhibitory concentration(IC50)of 5-FU on the parent line HCT-116 and drug-resistant line HCT-116/5-FU.The cell growth curve was established for the calculation of population doubling time(TD).The mRNA levels and protein levels of RUNX3,P-glycoprotein(P-gp),multidrug resistance-associated protein 1(MRP1),and lung resistance-related protein(LRP)in HCT-116 and HCT-116/5-FU cells were determined by qRT-PCR and Western blotting,respectively.The RUNX3 expression in HCT-116 cells was knocked down by siRNA technique,and the cells were divided into RUNX3 knockdown groups(si-RUNX3-1 group and si-RUNX3-2 group)and negative control group(si-NC group).The knockdown efficiency was verified by qRT-PCR at the mRNA level and Western blotting at the protein level.The IC50 in si-RUNX3 groups and si-NC group was determined with CCK-8 method,and the expression of P-gp,MRP1,and LRP in the two groups was detected by Western blotting.Results A stable human colon cancer drug-resistant cell line HCT-116/5-FU was successfully constructed.HCT-116/5-FU showed the TD 1.38 times as long as that of HCT-116(P=0.002)and changed morphology.The mRNA level of RUNX3 in HCT-116/5-FU cells was significantly lower than that in HCT-116 cells(P=0.048),and those of P-gp(P=0.008),MRP1(P=0.001),and LRP(P=0.001)showed the opposite trend.The protein level of RUNX3 in HCT-116/5-FU cells was significantly lower than that in HCT-116(P<0.001),and those of P-gp,MRP1,and LRP presented the opposite trend(all P<0.001).The HCT-116 cell model with low expression of RUNX3 was successfully established.The mRNA level of RUNX3 had no significant difference between si-RUNX3-1 group and si-NC group(P=0.064),while the level in si-RUNX3-2 group was significantly lower than that in si-NC group(P=0.034).The protein levels of RUNX3 in si-RUNX3-1 group and si-RUNX3-2 group were lower than that in si-NC group(both P<0.001).The results demonstrated higher knocking efficiency in si-RUNX3-2 group,which was thus selected to complete the follow-up test.The IC50 of si-RUNX3 group was significantly higher than that of si-NC group(P<0.001),which indicated that the down-regulated expression of RUNX3 could reduce the sensitivity of HCT-116 cells to 5-FU.The relative protein levels of P-gp,MRP1,and LRP in si-RUNX3 group were significantly higher than those in si-NC group(all P<0.001).Conclusion The down-regulation of RUNX3 expression can reduce the sensitivity of HCT-116 cells to 5-FU,which is considered to be related to the up-regulated expression of P-gp,MRP1,and LRP.

[Irreducible Indirect Inguinal Hernia Caused by Sigmoid Colon Cancer Entering Right Groin:A Case Report].

We reported a case of irreducible indirect inguinal hernia caused by sigmoid colon cancer entering the right groin.The patient complained about a right groin mass for more than 60 years with progressive enlargement for 3 years and pain for half a month.Abdominal CT examination at admission showed rectum and sigmoid colon hernia in the right inguinal area and thickening of sigmoid colon wall.Electronic colonoscopy and pathological diagnosis showed sigmoid colon cancer.Therefore,the result of preliminary diagnosis was irreducible indirect inguinal hernia caused by sigmoid colon cancer entering the right groin.We converted laparoscopic exploration to laparotomy followed by radical sigmoidectomy and employed end-to-end anastomosis of descending colon and rectum in combination with repair of right inguinal hernia.The patient recovered well after operation and was discharged.

Long noncoding RNA HOTAIR silencing inhibits invasion and proliferation of human colon cancer LoVo cells via regulating IGF2BP2.

Colon cancer is one of the most life-threatening malignancies worldwide. Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) is a cancer-associated biomarker involved in the metastasis and prognosis of several cancers. However, whether and how HOTAIR affects colon cancer progression is still unclear. Consequently, we used RNA interference to knock down HOTAIR to explore its effects on human colon cancer cells. The dual luciferase reporter gene assay was initially used for testify the regulating relationship between lncRNA HOTAIR and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). We determined the expressions of HOTAIR, IGF2BP2, E-cadherin, and vimentin. Meanwhile, cell growth, cycle and apoptosis, migration, and invasion were assayed. LoVo cells were transplanted into nude mice, and tumor formation and microvessel density were evaluated. LncRNA HOTAIR positively regulated IGF2BP2. Besides, the expressions of HOTAIR and E-cadherin and the apoptosis were increased, while the expressions of IGF2BP2 and vimentin, the growth, invasion and migration of LoVo cells, the average tumor weight, and microvessel density value were decreased. Of importance, overexpressed IGF2BP2 could reverse the above impacts. Taken together, the current study indicates that silencing of HOTAIR could inhibit the invasion, proliferation, and migration, and promote apoptosis of colon cancer LoVo cells through suppressing IGF2BP2 and the epithelial-mesenchymal transition.

Effects of Glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-ß/PI3K-AKT-mTOR signaling pathway.

This study aims to investigate the effects of glucose transport l (Glut1) gene on proliferation, differentiation, and apoptosis of colorectal cancer (CRC) cells by regulating the TGF-ß/PI3K-AKT-mTOR signaling pathway. Immunohistochemistry was conducted to detect the positive Glut1 expression. Normal human CRC epithelial cells (CCD-18Co) and CRC cell line HCT116 were grouped into the control, blank, negative control (NC), and shGlut1-1 groups. RT-qPCR and Western blotting were performed to detect the expressions of Glut1, TGF-ß1, PI3K, AKT, PTEN, mTOR, Bcl-2, and Bax. Protein expression of phosphorylated-PI3K (p-PI3K), p-S473-AKT, p-S389-S6K1, p-T70-4EBP1, Cleaved caspase-3 and Cleaved-PARP were detected. MTT assay, flow cytometry, and colony formation assay were performed in order to detect cell viability, cell cycle, and apoptosis, respectively. The positive expression rate of Glut1 in CRC tissues was 75% ± 8%, while in the adjacent normal tissues it was 0%. In comparison to adjacent normal tissues, CRC tissues had increased Glut1, TGF-ß1, PI3K, AKT, mTOR, and Bcl-2 expressions, and p-PI3K, p-S473-AKT, p-S389-S6K1, and p-T70-4EBP1 expressions; and decreased PTEN, Bax, Cleaved caspase-3, and Cleaved-PARP expressions. In comparison with the blank and NC groups, cells in the shGlut1-1 group showed decreased Glut1, TGF-ß1, PI3K, AKT, mTOR, and Bcl-2 expressions, and p-PI3K, p-S473-AKT, p-S389-S6K1, and p-T70-4EBP1 expressions; and increased PTEN, Bax, Cleaved caspase-3, and Cleaved-PARP expressions, along with more arrested cells in C0/C1 phase than in S phase and slower cell growth. These results suggested that silencing the Glut1 gene inhibited proliferation and promoted apoptosis of CRC cells by inactivating TGF-ß/PI3K-AKT-mTOR signaling pathway.

Expressions of Inhibitors of DNA Binding-1 and Matrix Metalloproteinase-9 in Colorectal Adenocarcinoma Tissues and Their Correlations with Microvessel Density.

Objective To explore the expressions of inhibitors of DNA binding-1 (Id-1) and matrix metalloproteinase-9 (MMP-9) in colorectal carcinoma tissues and its correlation with microvessel density (MVD). Methods The expressions of Id-1 and MMP-9 as well as CD34-labelled MVD in colorectal adenocarcinoma tissues (n=50) and normal adjacent tissues (n=50) were examined by immunohistochemistry. Results The positive expressions of Id-1 and MMP-9 were seen in 72.00% (36/50) and 78.00%(39/50) of colorectal adenocarcinoma tissues,which were significantly higher than those [24.00%(12/50) and 28.00% (14/50)] in normal adjacent tissues (P=0.000). The MVD value (17.22±2.08) in colorectal adenocarcinoma tissues was significantly higher than that (5.36±2.17) in normal adjacent tissues (P=0.000). The expressions of Id-1 and MMP-9 and MVD were significantly correlated with serosa invasion,TNM stage,carcinoembryonic antigen(+),lymph node metastasis,vascular invasion,and liver metastasis (all P<0.05) but not with the patient's age,gender,tumor size,and differentiation degree (all P>0.05). The MVD value with Id-1 and MMP-9 positive expression were significantly higher than those with Id-1 and MMP-9 negative expression (all P=0.000). The expression of Id-1 in colorectal adenocarcinoma tissues showed significantly positive correlation with that of MMP-9 (r=0.429,P=0.000). Cox multivariate analysis showed that Id-1 and MMP-9 expressions were independent prognostic factors for colorectal carcinoma. Conclusions The high expressions of Id-1 and MMP-9 have high correlations with the development and progression of colorectal adenocarcinoma and have positive correlation with MVD. Both of them may be involved in the microvascular generation and the invasion and hematogenous metastasis of colorectal carcinoma.

Global trends of single cell sequence associated in cancer from 2011 to 2024: A bibliometric analysis.

Objective: Exploring the different molecular and clinicopathological features of nodal cancer based on single cell sequencing can reveal the intertumoral heterogeneity in cancer, and provide new ideas for early diagnosis, treatment and prognosis analysis of cancer. Methods: The hotspots, the features of worldwide scientific output, and the frontiers concerning single cell sequence related to cancer from 2011 to 2024 were determined using our bibliometric analysis. Web of Science Core Collection (WOSCC) database was searched for publications on single cell sequence associated with cancer that were published between 2011 and 2024. According to the journals, keywords, number of records, affiliations, citations, and countries, we conducted a bibliometric analysis. With the use of the data gathered from the WOSCC, geographic distribution was visualized, keyword, affiliation, and author cluster analyses were conducted, and co-cited references were reviewed and a descriptive analysis was also performed. Results: From the analysis, it was concluded that 6189 articles that were published between 2011 and 2024 in total were identified. Frontiers in immunology is the leading journal with the most publications in field of the research. The five clusters that were identified for hotspots included immunotherapy, single-cell RNA sequencing, hepatocellular carcinoma, proliferation, gene expression appeared the most frequently. Journals, nations, organizations, scholars with most contribution and most referenced publications globally were extracted. Studies have mostly concentrated on the spatial transcriptomics, pan-cancer analysis, hepatocellular carcinoma et al. Conclusion: Single-cell sequencing plays a significant role in tumor diagnosis, treatment and prognosis.

PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression.

OBJECTIVE: This inquiry endeavors to delineate the influence of PDIA3 on tumor-associated macrophages within the realm of colorectal malignancies, whilst elucidating the intrinsic biochemical pathways. METHOD: Leveraging bioinformatics, we scrutinized the symbiosis between PDIA3, STAT3, and CD274. A xenograft model in immunodeficient murine served to assess PDIA3's impact on colorectal carcinogenesis. Further, Western blot analysis quantified the protein expression of PDIA3, p-STAT3, PD-1, XBP-1, assorted enzymes, and IL-6. Moreover, in vitro assays gauged SW480 cellular dynamics inclusive of migration, invasive potential, and proliferation. RESULTS: Bioinformatics exploration exposed PDIA3's elevated presence in diverse cancers, with a marked expression in colorectal cancer, as per TCGA and GEO repositories. Correlative studies showed PDIA3 positively aligning with STAT3 and CD274, the latter also associated with monocyte-derived macrophages. Comparative analysis of colorectal neoplasms and normal colon samples unveiled heightened levels of PDIA3 markers which, when overexpressed in SW480 cells, escalated tumorigenicity and oncogenic behaviors, with a noted decrease upon PD-1 monoclonal antibody intervention. CONCLUSIONS: PDIA3 augments the M2 polarization of tumor-associated macrophages via modulation of the STAT3/PD-1 cascade, thus invigorating the tumorous proliferation and dissemination in colorectal cancer. Such revelations position PDIA3 as an auspicious target for PD-1 blockade therapeutics, offering a promising foundation for rectifying colorectal carcinoma.

Immune checkpoint inhibitors in colorectal cancer: limitation and challenges.

Colorectal cancer exhibits a notable prevalence and propensity for metastasis, but the current therapeutic interventions for metastatic colorectal cancer have yielded suboptimal results. ICIs can decrease tumor development by preventing the tumor's immune evasion, presenting cancer patients with a new treatment alternative. The increased use of immune checkpoint inhibitors (ICIs) in CRC has brought several issues. In particular, ICIs have demonstrated significant clinical effectiveness in patients with MSI-H CRC, whereas their efficacy is limited in MSS. Acquired resistance can still occur in patients with a positive response to ICIs. This paper describes the efficacy of ICIs currently in the clinical treatment of CRC, discusses the mechanisms by which acquired resistance occurs, primarily related to loss and impaired presentation of tumor antigens, reduced response of IFN-λ and cytokine or metabolic dysregulation, and summarizes the incidence of adverse effects. We posit that the future of ICIs hinges upon the advancement of precise prediction biomarkers and the implementation of combination therapies. This study aims to elucidate the constraints associated with ICIs in CRC and foster targeted problem-solving approaches, thereby enhancing the potential benefits for more patients.

Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy.

BACKGROUND: Oxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism. METHODS: Two colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin. RESULTS: CCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine. CONCLUSIONS: Research on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.

Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization.

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Discovery of a long-ranged charge order with 1/4 Ge1-dimerization in an antiferromagnetic Kagome metal.

Exotic quantum states arise from the interplay of various degrees of freedom such as charge, spin, orbital, and lattice. Recently, a short-ranged charge order (CO) was discovered deep inside the antiferromagnetic phase of Kagome magnet FeGe, exhibiting close relationships with magnetism. Despite extensive investigations, the CO mechanism remains controversial, mainly because the short-ranged behavior hinders precise identification of CO superstructure. Here, combining multiple experimental techniques, we report the observation of a long-ranged CO in high-quality FeGe samples, which is accompanied with a first-order structural transition. With these high-quality samples, the distorted 2 × 2 × 2 CO superstructure is characterized by a strong dimerization along the c-axis of 1/4 of Ge1-sites in Fe3Ge layers, and in response to that, the 2 × 2 in-plane charge modulations are induced. Moreover, we show that the previously reported short-ranged CO might be related to large occupational disorders at Ge1-site, which upsets the equilibrium of the CO state and the ideal 1 × 1 × 1 structure with very close energies, inducing nanoscale coexistence of these two phases. Our study provides important clues for further understanding the CO properties in FeGe and helps to identify the CO mechanism.

Exosomes: Another intercellular lipometabolic communication mediators in digestive system neoplasms?

Neoplasms are one of the most concerned public health problems worldwide. Digestive system neoplasms, with a high morbidity and mortality, is one of the most common malignant tumors in human being. It is found that exosomes act as an intercellular communication media to carry the metabolic and genetic information of parental cells to target cells. Likely, exosomes participate in lipid metabolism and regulates multiple processes in digestive system neoplasms, including the information transmission among cancer cells, the formation of neoplastic microenvironment, and the neoplastic biological behaviors like metastasis, invasion, and the chemotherapy resistance. In this review, we firstly introduce the main mechanisms whereas exosomes act as intercellular lipometabolic communication mediator in digestive system neoplasms. Thereafter we introduce the relationship between exosomes lipid metabolism and various type of digestive system neoplasms, including gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. Eventually, we summarized and prospected the development and implication of exosomes in digestive system neoplasms. The further research of exosomes as intercellular lipid metabolism mediator will contribute to accurate and efficient diagnosis and treatment of digestive system neoplasms.

Novel Design and Evaluation of Redirection Controllers Using Optimized Alignment and Artificial Potential Field.

Redirected walking allows users to naturally locomote within virtual environments that are larger than or different in layout from the physically tracked space. In this paper, we proposed novel optimization-driven alignment-based and Artificial Potential Field (APF) redirected walking controllers, as well as an integrated version of the two. The first two controllers employ objective functions of one variable, which is the included angle between the user's heading vector and the target vector originating from the user's physical position. The optimized angle represents the physical cell that is best aligned with the virtual cell or the target vector on which the designated point has the minimum APF value. The derived optimized angle is used to finely set RDW gains. The two objective functions can be optimized simultaneously, leading to an integrated controller that is potentially able to take advantage of the alignment-based controller and APF-based controller. Through extensive simulation-based studies, we found that the proposed alignment-based and integrated controllers significantly outperform the state-of-the-art controllers and the proposed APF based controller in terms of the number of resets. Furthermore, the proposed alignment controller and integrated controller provide a more uniform likelihood distribution across distance between resets, as compared to the other controllers.