Trends in colorectal cancer screening compliance and incidence among 60- to 74-year-olds in China.

BACKGROUND: Compliance with colonoscopy among elderly individuals participating in colorectal cancer (CRC) screening programs is unsatisfactory, despite a high detection rate of bowel-related diseases. In this study, our aim was to analyze the impact of risk factors on the trends of compliance and detection rates in colonoscopy among high-risk individuals aged 60-74. METHODS: A retrospective study was conducted on the high-risk individuals aged 60-74 participating in the 2021 CRC screening program in Tianjin, China. Logistic regression analyses, including both univariate and multivariate analyses, were performed to explore the impact of different risk factors on colonoscopy compliance among the high-risk individuals. Besides, the study investigated the influence of various risk factors on the detection rates of bowel-related diseases among the high-risk individuals who underwent colonoscopy. RESULTS: A total of 24,064 high-risk individuals were included, and 5478 individuals received a free colonoscopy, with an overall compliance of 22.76%. Among them, the adenoma detection rate was 55.46%. Males and individuals with a positive FIT had high compliance and detection rates for CRC, advanced adenomas (AA), advanced colorectal neoplasia (ACN), and colorectal neoplasm (CN). Individuals aged 70-74 were associated with low compliance but high CRC, ACN, and CN detection rates. Individuals who reported a history of chronic constipation, bloody mucous, and CRC in first-degree relative showed high compliance but no significantwere associated with the detection rates of CRC, AA, and CN. CONCLUSION: This study reported several risk factors associated with the screening behaviors for CRC. Patterns and trends in CRC, AA, ACN, and CN compliance and detection rates correlate with risk factors.

Hydrogen sulfide improves endothelial barrier function by modulating the ubiquitination degradation of KLF4 through TRAF7 S-sulfhydration in diabetic aorta.

Anomalous vascular endothelium significantly contributes to various cardiovascular diseases. VE-cadherin plays a vital role in governing the endothelial barrier. Krüppel-like factor 4(KLF4), as a transcription factor, which binds the VE-cadherin promoter and enhances its transcription. Tumor necrosis factor receptor-associated factor 7 (TRAF7) is an E3 ubiquitin ligase that has been shown to modulate the degradation of KLF4. H2S can covalently modify cysteine residues on proteins through S-sulfhydration, thereby influencing the structure and functionality of the target protein. However, the role of S-sulfhydration on endothelial barrier integrity remains to be comprehensively elucidated. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates endothelial integrity and its underlying mechanism. In this study, we observed that protein S-sulfhydration was reduced in the endothelium during diabetes and TRAF7 was the main target. Overexpression of TRAF7-Cys327 mutant could mitigate the endothelial barrier damage by weakening TRAF7 interaction with KLF4 and reducing ubiquitination degradation of KLF4. In conclusion, our research demonstrates that H2S plays a pivotal role in regulating S-sulfhydration of TRAF7 at Cys327. This regulation effectively inhibits the ubiquitin-mediated degradation of KLF4, resulting in an upregulation of VE-cadherin levels. This molecular mechanism contributes to the prevention of endothelial barrier damage.

MITF regulates the subcellular location of HIF1α through SUMOylation to promote the invasion and metastasis of daughter cells derived from polyploid giant cancer cells.

High concentrations of cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs) in various tumors, which can produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric division. To study the role of hypoxia­inducible factor (HIF) 1α in the formation of PGCCs, colon cancer cell lines Hct116 and LoVo were used as experimental subjects. Western blotting, nuclear and cytoplasmic protein extraction and immunocytochemical experiments were used to compare the changes in the expression and subcellular localization of HIF1α, microphthalmia­associated transcription factor (MITF), protein inhibitor of activated STAT protein 4 (PIAS4) and von Hippel­Lindau disease tumor suppressor (VHL) after treatment with CoCl2. The SUMOylation of HIFα was verified by co­immunoprecipitation assay. After inhibiting HIF1α SUMOylation, the changes in proliferation, migration and invasion abilities of Hct116 and LoVo were compared by plate colony formation, wound healing and Transwell migration and invasion. In addition, lysine sites that led to SUMOylation of HIF1α were identified through site mutation experiments. The results showed that CoCl2 can induce the formation of PGCCs with the expression level of HIF1α higher in treated cells than in control cells. HIF1α was primarily located in the cytoplasm of control cell. Following CoCl2 treatment, the subcellular localization of HIF1α was primarily in the nuclei of PGCCs with daughter cells (PDCs). After treatment with SUMOylation inhibitors, the nuclear HIF1α expression in PDCs decreased. Furthermore, their proliferation, migration and invasion abilities also decreased. After inhibiting the expression of MITF, the expression of HIF1α decreased. MITF can regulate HIF1α SUMOylation. Expression and subcellular localization of VHL and HIF1α did not change following PIAS4 knockdown. SUMOylation of HIF1α occurs at the amino acid sites K391 and K477 in PDCs. After mutation of the two sites, nuclear expression of HIF1α in PDCs was reduced, along with a significant reduction in the proliferation, migration and invasion abilities. In conclusion, the post­translation modification regulated the subcellular location of HIF1α and the nuclear expression of HIF1α promoted the proliferation, migration and invasion abilities of PDCs. MITF could regulate the transcription and protein levels of HIF1α and participate in the regulation of HIF1α SUMOylation.

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis.

Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

Liquid Metal Composites-Enabled Real-Time Hand Gesture Recognizer with Superior Recognition Speed and Accuracy.

Prosthetic hands play a vital role in restoring forearm functionality for patients who have suffered hand loss or deformity. The hand gesture intention recognition system serves as a critical component within the prosthetic hand system. However, accurately and swiftly identifying hand gesture intentions remains a challenge in existing approaches. Here, a real-time motion intention recognition system utilizing liquid metal composite sensor bracelets is proposed. The sensor bracelet detects pressure signals generated by forearm muscle movements to recognize hand gesture intent. Leveraging the remarkable pressure sensitivity of liquid metal composites and the efficient classifier based on the optimized recognition algorithm, this system achieves an average offline and real-time recognition accuracy of 98.2% and 92.04%, respectively, with an average recognition speed of 0.364 s. Thus, this wearable system shows advantages in superior recognition speed and accuracy. Furthermore, this system finds applications in master-slave control of prosthetic hands in unmanned scenarios, such as electrically powered operations, space exploration, and telemedicine. The proposed system promises significant advances in next-generation intent-controlled prosthetic hands and robots.

14-3-3ε: a protein with complex physiology function but promising therapeutic potential in cancer.

Over the past decade, the role of the 14-3-3 protein has received increasing interest. Seven subtypes of 14-3-3 proteins exhibit high homology; however, each subtype maintains its specificity. The 14-3-3ε protein is involved in various physiological processes, including signal transduction, cell proliferation, apoptosis, autophagy, cell cycle regulation, repolarization of cardiac action, cardiac development, intracellular electrolyte homeostasis, neurodevelopment, and innate immunity. It also plays a significant role in the development and progression of various diseases, such as cardiovascular diseases, inflammatory diseases, neurodegenerative disorders, and cancer. These immense and various involvements of 14-3-3ε in diverse processes makes it a promising target for drug development. Although extensive research has been conducted on 14-3-3 dimers, studies on 14-3-3 monomers are limited. This review aimed to provide an overview of recent reports on the molecular mechanisms involved in the regulation of binding partners by 14-3-3ε, focusing on issues that could help advance the frontiers of this field. Video Abstract.

Prevalence and risk factors of colorectal neoplasia in individuals aged 40-49 years: Findings from screening program in China.

BACKGROUND AND AIM: The incidence of colorectal cancer (CRC) in individuals under 50 is increasing worldwide. We conducted an analysis of colonoscopy findings in high-risk individuals under 50 in the CRC screening program in Tianjin, China, to determine the detection rate and risk factors of advanced adenomas (AA), advanced colorectal neoplasia (ACN), colorectal neoplasia (CN). METHODS: Our study investigated individuals aged 40-49 who underwent CRC screening and completed colonoscopy, 2012-2020, while the 50-54 age group served as a control. We compared the detection rates of AA, ACN, and CN among three age groups using univariate and multivariable logistic regression analyses, and investigated the risk factors associated with AA, ACN, and CN among individuals aged 40-49. RESULTS: We found a gradual increase in the detection rate of AA, ACN, and CN among individuals aged 40-54. The detection rates for AA (OR 0.58; 95% CI 0.41-0.81), ACN (OR 0.58; 95% CI 0.43-0.77), and CN (OR 0.64; 95% CI 0.56-0.74) were lower in individuals aged 40-44 compared to 45-49. The detection rates of AA (OR 1.08; 95% CI 0.87-1.34) and ACN (OR 1.12; 95% CI 0.93-1.35) in individuals aged 45-49 were comparable with 50-54. Besides, lifestyle factors, BMI, and FIT are not associated with the detection rates of AA, ACN, and CN among individuals aged 40-49. CONCLUSIONS: Our study reveals screening data in individuals under 50, indicating comparable detection rates of AA and ACN in individuals aged 45-49 and 50-54. These findings provide valuable data support for optimizing the optimal age to initiate screening.

Fecal Immunochemical Testing and the Risk of Advanced Colorectal Neoplasia: A Difference-In-Difference Analysis.

PURPOSE: To evaluate the effectiveness of fecal immunochemical testing (FIT) in colorectal cancer screening. METHODS: We conducted a prospective cohort study among 5,598 participants age 40-74 years between 2012 and 2020 in Tianjin, China. Inverse probability weighting was adopted to adjust for potential imbalanced factors between groups. A Cox proportional hazards model was used to estimate the weighted associations between FIT screening and advanced colorectal neoplasia. A difference-in-difference (DID) model was adopted to compare the incidence rates of advanced colorectal neoplasia between groups. RESULTS: In DID analysis, the rate of incidence was reduced by 0.34 cases per person-years in the screening group as compared with the historical FIT screening group (rate ratio [RR], 0.08 [95% CI, 0.07 to 0.10]) and by 0.06 cases per person-years in the non-FIT screening group as compared with the historical non-FIT screening group (RR, 0.37 [95% CI, 0.29 to 0.48]; P < .001 for both comparisons), with a relative reduction of 0.28. Similar benefit effect from FIT screening was observed in sex and age subgroups. CONCLUSION: FIT screening was associated with a reduction in incidence density from advanced colorectal neoplasia.

Accurate Cancer Screening and Prediction of PD-L1-Guided Immunotherapy Efficacy Using Quantum Dot Nanosphere Self-Assembly and Machine Learning.

Accurate quantification of exosomal PD-L1 protein in tumors is closely linked to the response to immunotherapy, but robust methods to achieve high-precision quantitative detection of PD-L1 expression on the surface of circulating exosomes are still lacking. In this work, we developed a signal amplification approach based on aptamer recognition and DNA scaffold hybridization-triggered assembly of quantum dot nanospheres, which enables bicolor phenotyping of exosomes to accurately screen for cancers and predict PD-L1-guided immunotherapeutic effects through machine learning. Through DNA-mediated assembly, we utilized two aptamers for simultaneous ultrasensitive detection of exosomal antigens, which have synergistic roles in tumor diagnosis and treatment prediction, and thus, we achieved better sample classification and prediction through machine-learning algorithms. With a drop of blood, we can distinguish between different cancer patients and healthy individuals and predict the outcome of immunotherapy. This approach provides valuable insights into the development of personalized diagnostics and precision medicine.

Cytokeratin 7 Expression and Mismatch Repair Status for Survival Prediction in Patients With Low Rectal Cancer After Neoadjuvant Therapy.

BACKGROUND: More than half of the patients with locally advanced low rectal cancer exhibit no or minor response to nCRT. It is important to investigate the predictive and prognostic values of potential biomarkers in patients with locally advanced low rectal cancer receiving nCRT. MATERIALS AND METHODS: This retrospective study included 162 patients with locally advanced low rectal cancer who underwent nCRT, followed by total mesorectal excision (TME) between 2016 and 2019. Cytokeratin 7 (CK7) expression and mismatch repair (MMR) status were determined by immunohistochemistry (IHC). Categorical variables were compared using the chi-square test. Overall survival (OS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier and Cox methods. RESULTS: There were predominance significant differences in distance from anus margin (P < .0001) and circumferential extent of the tumor (P < .0001).CK7 positive expression was detected in 21 of the 162 patients (13%). The univariate and multivariate analysis revealed that patients whose tumors had CK7 positive expression had significantly shorter OS (HR = 3.878, P = .038; HR = 1.677, P = .035) and DFS (HR = 3.055, P = .027;HR = 3.569, P = .038) than those with CK7 negative expression. While patients with CK7 positive expression had a higher proportion of worse TRG compared with CK7 negative patients (P = .001). Patients with deficient mismatch repair (dMMR) just occupied a small proportion (8.6%), but there was still a close connection between the MMR status and recurrence after TME (P = .045). MMR status was an independent risk factor affecting the OS (HR = .307, P < .0001; HR = .123, P < .0001) and DFS (HR = .288, P < .0001; HR = .286, P < .0001) by univariate and multivariate analysis. But no significant difference in the proportion of TRG was observed between patients with dMMR and pMMR (P = .920). CONCLUSIONS: The result confirms negative prognostic role of CK7-positive and dMMR statuses, which have potential predictive value for neoadjuvant chemoradiotherapy response. This provides opportunity to modify individualized treatment strategies for patients with different CK7 expression levels and dMMR statuses.

Molecular mechanism of vimentin nuclear localization associated with the migration and invasion of daughter cells derived from polyploid giant cancer cells.

BACKGROUND: Polyploid giant cancer cells (PGCCs), a specific type of cancer stem cells (CSCs), can be induced by hypoxic microenvironments, chemical reagents, radiotherapy, and Chinese herbal medicine. Moreover, PGCCs can produce daughter cells that undergo epithelial-mesenchymal transition, which leads to cancer recurrence and disseminated metastasis. Vimentin, a mesenchymal cell marker, is highly expressed in PGCCs and their daughter cells (PDCs) and drives migratory persistence. This study explored the molecular mechanisms by which vimentin synergistically regulates PGCCs to generate daughter cells with enhanced invasive and metastatic properties. METHODS: Arsenic trioxide (ATO) was used to induce the formation of PGCCs in Hct116 and LoVo cells. Immunocytochemical and immunohistochemical assays were performed to determine the subcellular localization of vimentin. Cell function assays were performed to compare the invasive metastatic abilities of the PDCs and control cells. The molecular mechanisms underlying vimentin expression and nuclear translocation were investigated by real-time polymerase chain reaction, western blotting, cell function assays, cell transfection, co-immunoprecipitation, and chromatin immunoprecipitation, followed by sequencing. Finally, animal xenograft experiments and clinical colorectal cancer samples were used to study vimentin expression in tumor tissues. RESULTS: Daughter cells derived from PGCCs showed strong proliferative, migratory, and invasive abilities, in which vimentin was highly expressed and located in both the cytoplasm and nucleus. Vimentin undergoes small ubiquitin-like modification (SUMOylation) by interacting with SUMO1 and SUMO2/3, which are associated with nuclear translocation. P62 regulates nuclear translocation of vimentin by controlling SUMO1 and SUMO2/3 expression. In the nucleus, vimentin acts as a transcription factor that regulates CDC42, cathepsin B, and cathepsin D to promote PDC invasion and migration. Furthermore, animal experiments and human colorectal cancer specimens have confirmed the nuclear translocation of vimentin. CONCLUSION: P62-dependent SUMOylation of vimentin plays an important role in PDC migration and invasion. Vimentin nuclear translocation and overexpressed P62 of cancer cells may be used to predict patient prognosis, and targeting vimentin nuclear translocation may be a promising therapeutic strategy for metastatic cancers.

Exogenous H2S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts.

Excessive ROS accumulation contributes to cardiac injury in type 2 diabetes mellitus. Hydrogen sulfide (H2S) is a vital endogenous gasotransmitter to alleviate cardiac damage in diabetic cardiomyopathy (DCM). However, the underlying mechanisms remain unclear. In this study, we investigated the effects of NaHS administration in db/db mice via intraperitoneal injection for 20 weeks and the treatment of high glucose (HG), palmitate (PA) and NaHS in HL-1 cardiomyocytes for 48 h, respectively. H2S levels were decreased in hearts of db/db mice and HL-1 cardiomyocytes exposed to HG and PA, which were restored by NaHS. Exogenous H2S activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/glutathione (GSH) pathway, suppressed ferroptosis and mitigated mitochondrial apoptosis in db/db mice. However, these effects were abrogated after Nrf2 knockdown. NaHS treatment elevated the ubiquitination level of Kelch-like ECH-associated protein (Keap1) by preserving its E3 ligase synoviolin (Syvn1), resulting in Nrf2 nuclear translocation. H2S facilitated the sulfhydration of Syvn1-cys115 site, a post-translational modification. Transfecting Syvn1 C115A in cardiomyocytes exposed to HG and PA partially attenuated the effects of NaHS on Nrf2 and cell death. Our findings suggest that exogenous H2S regulates Nrf2/GPx4/GSH pathway by promoting the Syvn1-Keap1 interaction to reduce ferroptosis and mitochondrial apoptosis in DCM.

Exogenous H2 S promotes ubiquitin-mediated degradation of SREBP1 to alleviate diabetic cardiomyopathy via SYVN1 S-sulfhydration.

BACKGROUND: Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate molecular mechanisms governing the aberrant accumulation of lipid droplets within cardiomyocytes remain to be comprehensively elucidated. METHODS: Both obese diabetic (db/db) mice and HL-1 cells treated with 200 µmol/L palmitate and 200 µmol/L oleate were used to simulate type 2 diabetes conditions. Transmission electron microscopy is employed to assess the size and quantity of lipid droplets in the mouse hearts. Transcriptomics analysis was utilized to interrogate mRNA levels. Lipidomics and ubiquitinomics were employed to explore the lipid composition alterations and proteins participating in ubiquitin-mediated degradation in mice. Clinical data were collected from patients with diabetes-associated cardiomyopathy and healthy controls. Western blot analysis was conducted to assess the levels of proteins linked to lipid metabolism, and the biotin-switch assay was employed to quantify protein cysteine S-sulfhydration levels. RESULTS: The administration of H2 S donor, NaHS, effectively restored hydrogen sulfide levels in both the cardiac tissue and plasma of db/db mice (+7%, P < 0.001; +5%, P < 0.001). Both db/db mice (+210%, P < 0.001) and diabetic patients (+83%, P = 0.22, n = 5) exhibit elevated plasma triglyceride levels. Treatment with GYY4137 effectively lowers triglyceride levels in db/db mice (-43%, P = 0.007). The expression of cystathionine gamma-lyase and HMG-CoA reductase degradation protein 1 (SYVN1) was decreased in db/db mice compared with the wild-type mice (cystathionine gamma-lyase: -31%, P = 0.0240; SYVN1: -35%, P = 0.01), and NaHS-treated mice (SYVN1: -31%, P = 0.03). Conversely, the expression of sterol regulatory element-binding protein 1 (SREBP1) was elevated (+91%, P = 0.007; +51%, P = 0.03 compared with control and NaHS-treated mice, respectively), along with diacylglycerol O-acyltransferase 1 (DGAT1) (+95%, P = 0.001; +35%, P = 0.02) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) (+88%, P = 0.01; +22%, P = 0.32). Exogenous H2 S led to a reduction in lipid droplet formation (-48%, P < 0.001), restoration of SYVN1 expression, modification of SYVN1's S-sulfhydration status and enhancement of SREBP1 ubiquitination. Overexpression of SYVN1 mutated at Cys115 decreased SREBP1 ubiquitination and increased the number of lipid droplets. CONCLUSIONS: Exogenous H2 S enhances ubiquitin-proteasome degradation of SREBP1 and reduces its nuclear translocation by modulating SYVN1's cysteine S-sulfhydration. This pathway limits lipid droplet buildup in cardiac myocytes, ameliorating diabetic cardiomyopathy.

Regulatory T cells are associated with the tumor immune microenvironment and immunotherapy response in triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of distant metastasis, an extremely poor prognosis, and a high risk of death. Regulatory T cells (Tregs) contribute to the formation of a tumor immunosuppressive microenvironment, which plays an important role in the progression and treatment resistance of TNBC. Methods: A public single-cell sequencing dataset demonstrated increased infiltration of Tregs in TNBC tissues relative to normal breast tissue. Weighted gene co-expression network analysis was used to identify Treg infiltration-related modules for METABRIC TNBC samples. Subsequently, we obtained two Treg infiltration-associated clusters of TNBC by applying consensus clustering and further constructed a prognostic model based on this Treg infiltration-associated gene module. The ability of the selected gene in the prognostic model, thymidine kinase-1 (TK1), to promote the progression of TNBC was evaluated in vitro. Results: We concluded that two Treg infiltration-associated clusters had different prognoses and sensitivities to drugs commonly used in breast cancer treatment, and multi-omics analysis revealed that the two clusters had different copy number variations of key tumor progression genes. The 7-gene risk score based on TNBC Treg infiltration was a reliable prognostic indicator both in the training and validation cohorts. Moreover, patients with TNBC with high Treg infiltration-related scores lacked the activation of immune activation pathways and exhibited resistance to anti-PD1 immunotherapy. Knocking down TK1 led to impaired proliferation, migration, and invasion of TNBC cells in vitro. In addition, specimens from patients with TNBC with high TK1 expression showed significantly higher Treg infiltration in tumors. Results of spatial transcriptome analysis showed that TK1 positive cells mainly localize in tumor area, and Treg cell infiltration in TNBC tissues was associated with high expression of TK1. Pan-cancer analysis also demonstrated that TK1 is associated with poor prognosis and activation of proliferation pathways in multiple cancers. Discussion: We established a prognostic model related to Treg infiltration and this model can be used to establish a clinically relevant classification of TNBC progression. Additionally, our work revealed the underestimable potential of TK1 as a tumor biomarker and immunotherapeutic target.

Does an apple a day keep away diseases? Evidence and mechanism of action.

Apples and their products exemplify the recently reemphasized link between dietary fruit intake and the alleviation of human disease. Their consumption does indeed improve human health due to their high phytochemical content. To identify potentially relevant articles from clinical trials, some epidemiological studies and meta-analyses, and in vitro and in vivo studies (cell cultures and animal models), PubMed was searched from January 1, 2012, to May 15, 2022. This review summarized the potential effects of apple and apple products (juices, puree, pomace, dried apples, extracts rich in apple bioactives and single apple bioactives) on health. Apples and apple products have protective effects against cardiovascular diseases, cancer, as well as mild cognitive impairment and promote hair growth, healing of burn wounds, improve the oral environment, prevent niacin-induced skin flushing, promote the relief of UV-induced skin pigmentation, and improve the symptoms of atopic dermatitis as well as cedar hay fever among others. These effects are associated with various mechanisms, such as vascular endothelial protection, blood lipids lowering, anti-inflammatory, antioxidant, antiapoptotic, anti-invasion, and antimetastatic effects. Meanwhile, it has provided an important reference for the application and development of medicine, nutrition, and other fields.

Clinicopathological significance of vasculogenic mimicry and fetal hemoglobin expression in peripheral neuroblastic tumors in children.

PURPOSE: Vasculogenic mimicry (VM) is present in a variety of malignant tumors, and is related to the degree of malignancy. Neuroblastoma (NB) can induce the expression of fetal hemoglobin (HB-F). The purpose of this study was to investigate the clinicopathological significance of the number of VMs and tumor cell expression of HB-F in children with peripheral neuroblastic tumors (pNTs). MATERIALS AND METHODS: We collected tissue samples and clinical data from 101 children with pNTs; prepared serial sections of tissue wax blocks for hematoxylin and eosin staining, CD31/periodic acid-Schiff double staining, and HB-F immunohistochemical staining; and analyzed the experimental results. RESULTS: There were significant differences in the number of VMs and HB-F expression in tumor cells according to the pathological classification of pNTs (P<0.001, collectively). Poorly differentiated NB had a median of 137 VMs and 25.5% HB-F expression. Differentiating NB had a median of 90.5 VMs and 8.5% HB-F expression. Ganglioneuroblastoma intermixed had a median of 6.0 VMs and 1.0% HB-F expression. Ganglioneuromas had no VM and a median of 0% HB-F expression. The number of VMs and the expression of HB-F were significantly higher in the poor prognosis group than the good prognosis group (P<0.001, collectively). There was a strong positive correlation between the number of VMs and HB-F expression in pNTs (r=0.891, P<0.001). CONCLUSION: We confirmed VM and HB-F expression in pNTs. The number of VMs and HB-F expression were higher in poorly differentiated tumors. The number of VMs and level of HB-F expression in pNTs might be related to the prognosis.

The Role of Cathepsin B in Pathophysiologies of Non-tumor and Tumor tissues: A Systematic Review.

Cathepsin B (CTSB), a lysosomal cysteine protease, plays an important role in human physiology and pathology. CTSB is associated with various human diseases, and its expression level and activity are closely related to disease progression and severity. Physiologically, CTSB is integrated into almost all lysosome-related processes, including protein turnover, degradation, and lysosome-mediated cell death. CTSB can lead to the development of various pathological processes through degradation and remodeling of the extracellular matrix. During tumor development and progression, CTSB has two opposing effects. Its pro-apoptotic properties reduce malignancy, while its proteolytic enzymatic activity promotes invasion and metastasis, thereby inducing malignancy. Here, we discuss the roles of CTSB in tumor and non-tumor disease pathophysiologies. We conclude that targeting the activity or expression of CTSB may be important for treating tumor and non-tumor diseases.

Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway.

Introduction: Tientsin albino 2 (TA2) mice can develop spontaneous breast cancer (SBC), which is associated with multiple pregnancies and infection with the mouse mammary tumor virus (MMTV). In this study, we sought to elucidate the molecular mechanisms underlying the development of SBC in TA2 mice induced by MMTV. Methods: The integration site of MMTV in TA2 SBC was identified using whole-genome sequencing. The expression of fibroblast growth factor 3 (FGF3) in SBCs and normal breast tissues was compared. The primary cell line, TA-1106, derived from SBC, was cultured. The proliferation, cell cycle, migration, invasion, and tumorigenicity abilities, as well as the expression of epithelial-mesenchymal transition-related proteins, phosphorylated STAT3, and phosphorylated Akt, were assessed in MA-891cell line from TA2 and TA-1106 cells after FGF3 knockdown. The binding of FGF3 to FGF receptor 1 (FGFR1) was determined by co-immunoprecipitation. Additionally, the relationship between STAT3 and Akt phosphorylation was investigated using a small molecule inhibitor and STAT3 knockdown. Results: MMTV integrated upstream of the FGF3 gene, and the FGF3 protein was highly expressed in TA2 SBCs. FGF3 knockdown in MA-891 and TA-1106 decreased their proliferation, migration, and invasion abilities, affected the cell cycle and expression of epithelial-mesenchymal transition-related proteins, and inhibited the growth of animal xenografts. FGF3 binds to FGFR1, and either FGF3 or FGFR1 knockdown decreases STAT3 and Akt phosphorylation levels. Inhibition of phosphorylation or expression of STAT3 resulted in decreased Akt phosphorylation levels. Inhibition of Akt phosphorylation also resulted in decreased STAT3 phosphorylation levels. Furthermore, treatment of MA-891 and TA-1106 cells with Wortmannin or Stattic caused FGFR1 upregulation in addition to inhibiting Akt or STAT3 phosphorylation. Conclusion: The results of this study demonstrate that FGF3 plays a significant role in the development of SBC through the FGF3/FGFR1/STAT3 signaling pathway. There is a reciprocal activation between STAT3 and Akt. Inhibition of STAT3 or Akt phosphorylation promoted the expression of FGFR1. Validating the conclusions obtained in this study in human breast cancer (HBC) may contribute to targeted therapy and it is worth exploring whether the homologous sequences of MMTV in HBC have a similar oncogenic effect.

A 3D-Printed Ferromagnetic Liquid Crystal Elastomer with Programmed Dual-Anisotropy and Multi-Responsiveness.

Liquid crystal elastomers (LCE) and magnetic soft materials are promising active materials in many emerging fields, such as soft robotics. Despite the high demand for developing active materials that combine the advantages of LCE and magnetic actuation, the lack of independent programming of the LCE nematic order and magnetization in a single material still hinders the desired multi-responsiveness. In this study, a ferromagnetic LCE (magLCE) ink with nematic order and magnetization is developed that can be independently programmed to be anisotropic, referred to as "dual anisotropy", via a customized 3D-printing platform. The magLCE ink is fabricated by dispersing ferromagnetic microparticles in the LCE matrix, and a 3D-printing platform is created by integrating a magnet with 3-DoF motion into an extrusion-based 3D printer. In addition to magnetic fields, magLCEs can also be actuated by heating sources (either environmental heating or photo-heating of the embedded ferromagnetic microparticles) with a high energy density and tunable actuation temperature. A programmed magLCE strip robot is demonstrated with enhanced adaptability to complex environments (different terrains, magnetic fields, and temperatures) using a multi-actuation strategy. The magLCE also has potential applications in mechanical memory, as demonstrated by the multistable mechanical metastructure array with remote writability and stable memory.

Prognostic risk factors of serous ovarian carcinoma based on mesenchymal stem cell phenotype and guidance for therapeutic efficacy.

BACKGROUND: Epithelial ovarian cancer is the leading cause of death from gynecologic cancer, in which serous ovarian carcinoma (SOC) is the most common histological subtype. Although PARP inhibitors (PARPi) and antiangiogenics have been accepted as maintenance treatment in SOC, response to immunotherapy of SOC patients is limited. METHODS: The source of transcriptomic data of SOC was from the Cancer Genome Atlas database and Gene Expression Omnibus. The abundance scores of mesenchymal stem cells (MSC scores) were estimated for each sample by xCell. Weighted correlation network analysis is correlated the significant genes with MSC scores. Based on prognostic risk model construction with Cox regression analysis, patients with SOC were divided into low- and high-risk groups. And distribution of immune cells, immunosuppressors and pro-angiogenic factors in different risk groups was achieved by single-sample gene set enrichment analysis. The risk model of MSC scores was further validated in datasets of immune checkpoint blockade and antiangiogenic therapy. In the experiment, the mRNA expression of prognostic genes related to MSC scores was detected by real-time polymerase chain reaction, while the protein level was evaluated by immunohistochemistry. RESULTS: Three prognostic genes (PER1, AKAP12 and MMP17) were the constituents of risk model. Patients classified as high-risk exhibited worse prognosis, presented with an immunosuppressive phenotype, and demonstrated high micro-vessel density. Additionally, these patients were insensitive to immunotherapy and would achieve a longer overall survival with antiangiogenesis treatment. The validation experiments showed that the mRNA of PER1, AKAP12, and MMP17 was highly expressed in normal ovarian epithelial cells compared to SOC cell lines and there was a positive correlation between protein levels of PER1, AKAP12 and MMP17 and metastasis in human ovarian serous tumors. CONCLUSION: This prognostic model established on MSC scores can predict prognosis of patients and provide the guidance for patients receiving immunotherapy and molecular targeted therapy. Because the number of prognostic genes was fewer than other signatures of SOC, it will be easily accessible on clinic.