Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4.

Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.

Mining bone metastasis related key genes of prostate cancer from the STING pathway based on machine learning.

Background: Prostate cancer (PCa) is the second most prevalent malignant tumor in male, and bone metastasis occurs in about 70% of patients with advanced disease. The STING pathway, an innate immune signaling mechanism, has been shown to play a key role in tumorigenesis, metastasis, and cancerous bone pain. Hence, exploring regulatory mechanism of STING in PCa bone metastasis will bring novel opportunities for treating PCa bone metastasis. Methods: First, key genes were screened from STING-related genes (SRGs) based on random forest algorithm and their predictive performance was evaluated. Subsequently, a comprehensive analysis of key genes was performed to explore their roles in prostate carcinogenesis, metastasis and tumor immunity. Next, cellular experiments were performed to verify the role of RELA in proliferation and migration in PCa cells, meanwhile, based on immunohistochemistry, we verified the difference of RELA expression between PCa primary foci and bone metastasis. Finally, based on the key genes to construct an accurate and reliable nomogram, and mined targeting drugs of key genes. Results: In this study, three key genes for bone metastasis were mined from SRGs based on the random forest algorithm. Evaluation analysis showed that the key genes had excellent prediction performance, and it also showed that the key genes played a key role in carcinogenesis, metastasis and tumor immunity in PCa by comprehensive analysis. In addition, cellular experiments and immunohistochemistry confirmed that overexpression of RELA significantly inhibited the proliferation and migration of PCa cells, and RELA was significantly low-expression in bone metastasis. Finally, the constructed nomogram showed excellent predictive performance in Receiver Operating Characteristic (ROC, AUC = 0.99) curve, calibration curve, and Decision Curve Analysis (DCA) curve; and the targeted drugs showed good molecular docking effects. Conclusion: In sum, this study not only provides a new theoretical basis for the mechanism of PCa bone metastasis, but also provides novel therapeutic targets and novel diagnostic tools for advanced PCa treatment.

Changes in posterior corneal elevation after small incision lenticule extraction for different myopic diopters.

AIM: To study the changes and effect factors of posterior corneal surface after small incision lenticule extraction (SMILE) with different myopic diopters. METHODS: Ninety eyes of 90 patients who underwent SMILE were included in this retrospective study. Patients were allocated into three groups based on the preoperative spherical equivalent (SE): low myopia (SE≥-3.00 D), moderate myopia (-3.00 D>SE>-6.00 D) and high myopia (SE≤-6.00 D). Posterior corneal surfaces were measured by a Scheimpflug camera preoperatively and different postoperative times (1wk, 1, 3, 6mo, and 1y). Posterior mean elevation (PME) at 25 predetermined points of 3 concentric circles (2-, 4-, and 6-mm diameter) above the best fit sphere was analyzed. RESULTS: All surgeries were completed uneventfully and no ectasia was found through the observation. The difference of myopia group was significant at the 2-mm ring at 1 and 3mo postoperatively (1mo: P=0.017; 3mo: P=0.018). The effect of time on ΔPME was statistically significant (2-mm ring: P=0.001; 4-mm ring: P<0.001; 6-mm ring: P<0.001). The effect of different corneal locations on ΔPME was significant except 1wk postoperatively (1mo: P=0.000; 3mo: P=0.000; 6mo: P=0.001; 1y: P=0.001). Posterior corneal stability was linearly correlated with SE, central corneal thickness, ablation depth, residual bed thickness, percent ablation depth and percent stromal bed thickness. CONCLUSION: The posterior corneal surface changes dynamically after SMILE. No protrusion is observed on the posterior corneal surface in patients with different degrees of myopia within one year after surgery. SMILE has good stability, accuracy, safety and predictability.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Analysis of age-specified and genotype distribution of HPV multiple infections in the Chinese population.

Multiple infections are a key component of HPV pathogenesis and have a direct impact on how an infection turns out. It's crucial to look at the associations between HPV multiple infections and both age and HPV genotypes in the Chinese population, searching for the causative factors of multiple infections with a view to providing new ideas for the treatment and prevention of multiple infections. In this study, we retrospectively analyzed the data of HPV infections among outpatients from the 2019 year to the 2021 year of Shandong Maternal and Child Health Hospital. Analyzed the correlation between HPV multiple infections and age using logistic regression. Differences in the percentage of multiple infections between age groups were compared using the chi-square test. The chi-square test compared the differences in the distribution of 15 common HPV genotypes in mono- versus multiple infections. A two-dimensional matrix presented the frequency of HPV genotype combinations. Logistics regression analysis showed that age was significantly associated with the occurrence of multiple infections, with a dominance ratio OR 1.026 (95% CI 1.02-1.04). Interestingly, the proportion of HPV multiple infections among HPV-positive individuals increases with age in people older than 30 years of age. The chi-square test showed there was a difference in the distribution of HPV genotypes between multiple infections and mono- HPV infection (χ2 = 76.4; p = 0.000), a difference in the composition of HPV genotypes for dual versus single infections (χ2 = 90.6; p = 0.000) and a difference in HPV genotypes for triple versus single infections (χ2 = 56.7; p = 0.000). A 2 × 2 matrix showed that the combination of HPV52/HPV58 (30; 6.4%) was the combination of the highest frequency of infection for dual infections; The HPV52/HPV58 (21; 4.8%) combination was the highest frequency of HPV triple infection combination. HPV multiple infections were positively correlated with age; increasing age was positively correlated with the proportion of HPV multiple infections in the total infected population; the distribution of the 15 common genotypes of HPV differed between multiple infections and single infections; and HPV52:58 was a common type of infection combination in the Shandong population.

3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.

3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.

Rational design of a 'two-in-one' immunogen DAM drives potent immune response against mpox virus.

The global outbreak of the mpox virus (MPXV) in 2022 highlights the urgent need for safer and more accessible new-generation vaccines. Here, we used a structure-guided multi-antigen fusion strategy to design a 'two-in-one' immunogen based on the single-chain dimeric MPXV extracellular enveloped virus antigen A35 bivalently fused with the intracellular mature virus antigen M1, called DAM. DAM preserved the natural epitope configuration of both components and showed stronger A35-specific and M1-specific antibody responses and in vivo protective efficacy against vaccinia virus (VACV) compared to co-immunization strategies. The MPXV-specific neutralizing antibodies elicited by DAM were 28 times higher than those induced by live VACV vaccine. Aluminum-adjuvanted DAM vaccines protected mice from a lethal VACV challenge with a safety profile, and pilot-scale production confirmed the high yield and purity of DAM. Thus, our study provides innovative insights and an immunogen candidate for the development of alternative vaccines against MPXV and other orthopoxviruses.

Utility of the triglyceride-glucose index for predicting restenosis following revascularization surgery for extracranial carotid artery stenosis: A retrospective cohort study.

BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are effective interventions for treating extracranial carotid artery stenosis (ECAS), but long-term prognosis is limited by postoperative restenosis. Carotid restenosis is defined as carotid stenosis >50% by various examination methods in patients after carotid revascularization. This retrospective cohort study examined the value of the triglyceride-glucose (TyG) index for predicting vascular restenosis after carotid revascularization. METHODS: A total of 830 patients receiving CEA (408 cases, 49.2%) or CAS (422 cases, 50.8%) were included in this study. Patients were stratified into three subgroups according to TyG index tertile (high, intermediate, and low), and predictive value for restenosis was evaluated by constructing multivariate Cox proportional hazard regression models. RESULTS: Incidence of postoperative restenosis was significantly greater among patients with a high TyG index according to univariate analysis. Kaplan-Meier survival curve analysis revealed a progressive increase in restenosis prevalence with rising TyG index. Multivariate Cox regression models also identified TyG index as an independent predictor of restenosis, while receiver operating characteristic (ROC) curve analysis showed that TyG index predicted restenosis with moderate sensitivity (57.24%) and specificity (67.99%) (AUC: 0.619, 95% CI 0.585-0.652, z-statistic=4.745, p<0.001). Addition of the TyG index to an established risk factor model incrementally improved restenosis prediction (AUC: 0.684 (0.651-0.715) vs 0.661 (0.628-0.694), z-statistic =2.027, p = 0.043) with statistical differences. CONCLUSION: The TyG index is positively correlated with vascular restenosis risk after revascularization, which can be used for incremental prediction and has certain predictive value.

Robotic-assisted organ-preserving or parenchymal-sparing pancreatectomy in pancreatic benign or low-grade malignant tumors: a single institute's experience.

AIM: Robotic-assisted pancreatectomy has been widely used. Organ-preserving pancreatectomy (OPP) and parenchymal-sparing pancreatectomy (PSP) has been gradually adopted for pancreatic benign or low-grade malignant tumors. This study aimed to evaluate the safety and efficacy of robotic-assisted OPP/PSP in our institute. METHODS: Patients undergoing robotic-assisted OPS/PSP at First Affiliated Hospital of Sun Yat-sen University between July 2015 and October 2021 were included in this study. The short-term and long-term outcomes of patients were retrospectively analyzed. RESULTS: Seventy-two patients were enrolled, including spleen-preserving distal pancreatectomy, central pancreatectomy, duodenum-preserving pancreatic head resection, and enucleation. Patients included were more likely to be young female (female: 46/72, median age: 47 years old). The median intraoperative blood loss and operation time was 50 ml and 255 min, respectively. Clinically relevant postoperative pancreatic fistula was 20.8% (grade B: 15/72, 20.8%; no grade C). The overall complication rate was 22.2% with the median postoperative length-of-stay of 8 days. At a median follow-up time of 28.5 months, the 5-year overall survival and recurrence-free survival rate were 100.0% and 100.0%, respectively. CONCLUSION: The short-term and long-term outcomes of patients receiving robotic-assisted OPP/PSP were acceptable. Robotic-assisted OPP/PSP was a feasible and safe technique for pancreatic benign or low-grade malignant lesions.

Specific expression profile of follicular fluid-derived exosomal microRNAs in patients with diminished ovarian reserve.

BACKGROUND: Diminished ovarian reserve (DOR) is defined as a reduction in ovarian reserve and oocyte quality. The pathophysiology of DOR has not been completely explained as of yet. Scholars have uncovered a large number of exosomes that have been detected in follicular fluid, and exosomal miRNAs have been proven to play a critical role in controlling ovarian disorders and follicle formation. We focused on the expression profile of follicular fluid-derived exosomal microRNAs (miRNAs) and attempted to understand if their role is connected to the pathomechanism of DOR. METHODS: The follicular fluid-derived differentially expressed exosomal miRNAs (DEmiRs) between patients with DOR and those with normal ovarian function were investigated using the next-generation sequencing (NGS) method. The main metabolic and signaling pathways of DEmiRs were identified using the KEGG pathway database, disease ontology (DO) analysis, and gene ontology (GO) analysis. In the end, a Protein-Protein Interaction (PPI) network was built to search for exosomal miRNAs and their target genes that were potentially strongly connected with DOR. RESULTS: In comparison to normal controls, 52 DEmiRs were discovered in follicular fluid-derived exosomes of DOR patients, of which 19 were up-regulated and 33 were down-regulated (|log2(fold change) |>2, P < 0.05). GO, DO analysis, and the KEGG pathway database revealed that many of these DEmiRs have broad biological roles that are connected to ovarian function and disorders. The top ten DEmiRs in terms of expression were then chosen for miRNA-mRNA interaction analysis. Totally, 8 experimentally supported miRNAs (hsa-miR-1246, hsa-miR-483-3p, hsa-miR-122-5p, hsa-miR-130b-3p, hsa-miR-342-3p, hsa-miR-625-3p, hsa-miR-675-3p, and hsa-miR-134-5p) and 126 target genes were filtrated by utilizing Cytoscape software. The module analysis findings of the PPI network showed that the main module cluster with a score > 6.0 (MCODE score = 15) had six hub genes, including IGFR, VEGFA, KRAS, ERBB2, RHOA, and PTEN (MCODE score = 11.472). CONCLUSION: Our data suggested a special expression profile of follicular fluid-derived exosomal miRNAs in patients with DOR, which was probably correlated to ovarian dysfunction and follicle formation. These results may give a unique insight into a better understanding of the molecular process in the pathogenesis of DOR or other ovarian diseases.

Analysis of HPV prevalence among individuals with reproductive tract infections in a Chinese population.

The previous research has found that human papillomavirus (HPV) infection is the main cause of cervical cancer, but it is still unclear whether HPV infection, as well as the HPV genotypes, are related to reproductive tract infections in the Chinese population. Patients who underwent HPV screening at Shandong Maternal and Child Health Hospital were selected, and the HPV infection status was analyzed among patients with cervical lesions, bacterial vaginosis, cervical inflammation, fungal vaginitis, and pelvic infections. SPSS 22 statistical analysis was used to analyze the differences in HPV infection types and rates between the control group and the experimental group. The HPV infection rate of bacterial vaginosis (χ2 = 13.4; P < .001) and fungal vaginitis (χ2 = 3.3; P < .045) are both significantly different from the control group. The single HPV infections reveals significant differences from control group in bacterial vaginosis (χ2 = 7.3; P = .004), fungal vaginitis (χ2 = 4.5; P = .023), and cervical lesions (χ2 = 58.8; P < .001). In the bacterial infection group, HPV51 (1.9%; χ2 = 6.0; P = .008) and HPV58 (4.7%; χ2 = 3.3; P = .044) showed significant differences in infection compared to the control group. In the fungal infection group, HPV39 (2.7%; χ2 = 4.7; P = .032) showed a significant difference in infection compared to the control group. Cervical lesions, bacterial vaginosis, fungal vaginitis, and cervical lesions among Chinese population exhibit age-specified distribution. HPV infection rate in bacterial vaginitis, fungal vaginitis and cervical lesions was higher than that in normal group. HPV52 and HPV16 infection are different, and HPV39 is different between bacterial vaginitis and fungal vaginitis.

Renin-angiotensin system inhibitors improve the survival of cholangiocarcinoma: a propensity score-matched cohort study.

BACKGROUND: Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. METHODS: This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. RESULTS: Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32-0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20-0.79), respectively. Calcium channel blockers, diuretics, and ß-blockers didn't show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2-34.4); OS, 24.8 months (16.5-42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1-24.1); OS, 14.6 months (10.6-28.4)). The 1 year, 2 years, and 3 years' survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). CONCLUSIONS: RASis usage improves the survival of patients with CCA and hypertension concurrently.

Economic evaluation of four treatment strategies for postmenopausal patients with osteoporosis and a recent fracture in mainland China: a cost-effectiveness analysis.

Postmenopausal patients with osteoporosis who have a recent fracture are at very high risk of fracture, and this study finds that stratified treatment based on fracture risk would be a cost-effective treatment option for this population. PURPOSE: To evaluate the cost-effectiveness of four anti-osteoporosis medications (denosumab, zoledronate, teriparatide, and alendronate) for postmenopausal osteoporotic women in mainland China, using a stratified treatment strategy recommended by the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE). METHODS: A microsimulation Markov model was used to compare the cost-effectiveness of the four treatments in postmenopausal osteoporotic patients of different ages (65, 70, 75, and 80 years), with a recent fracture from the Chinese healthcare perspective. The primary outcome was the incremental cost-effectiveness ratio (ICER), which represent the incremental cost per quality-adjusted life-year (QALY) obtained. One-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness of model findings. RESULTS: Alendronate was dominated by denosumab-to-alendronate and zoledronate at all ages examined, indicating that the costs of the two drugs were lower, but QALYs was greater. However, teriparatide-to-alendronate yielded an ICER of $76,432.07/ QALY, compared with alendronate at age 65, which exceeded the pre-determined willingness-to-pay threshold of $37,653/ QALY. The results were similar at other ages. The DSA showed that the most sensitive parameters were drug efficacy for vertebral and wrist fractures, the relative risk of vertebral fractures, and the persistence of the drugs. The PSA showed that zoledronate had a 100% probability of being the most cost-effective treatment, with a willingness-to-pay threshold of $37,653/ QALY. CONCLUSION: Stratified treatment based on very high fracture risk is more cost-effective than conventional pills in mainland China. Among the stratified treatments, zoledronate is the optimal option.

Relationship between gastric xanthoma, gastric precancerous lesions, and gastric cancer: A retrospective study.

OBJECTIVE: To evaluate the relationship between gastric cancer and its precancerous lesions and gastric xanthoma. METHODS: Medical records of 47 736 patients who underwent gastroscopy in our center from January 2020 to December 2021 were reviewed. Patients' age, sex, endoscopic and histopathological findings, and the presence, number and location of gastric xanthoma were recorded. To investigate the detection rate of gastric xanthoma at different stages of gastric lesions, the participants were further divided into the chronic gastritis group (n = 42 758), the precancerous lesion group (n = 3672), and the gastric cancer group (n = 1306), respectively. RESULTS: The overall detection rate of gastric xanthoma was 2.85%, and it was most commonly observed in the gastric antrum (52.50%). In addition, gastric xanthoma was more common in men and more likely to be single lesion. It was most detected in the precancerous lesion group (8.39%), followed by the gastric cancer group (5.44%), and least in the chronic gastritis group (2.29%). Multivariate analysis showed that gastric xanthoma was closely related to precancerous lesions (odds ratio [OR] 3.197, 95% confidence interval [CI] 2.791-3.662, P < 0.001) and gastric cancer (OR 1.794, 95% CI 1.394-2.309, P < 0.001). CONCLUSION: Gastric xanthoma is closely related to gastric precancerous lesions and gastric cancer.

Targeted nutritional intervention with enhanced recovery after surgery for carotid endarterectomy: A prospective clinical trial.

Ischemic stroke is the most common cerebrovascular disease, and vascular obstruction is an important cause of this disease. As the main method for the management of carotid artery stenosis, carotid endarterectomy (CEA) is an effective and preventive treatment measure in ischemic cerebrovascular disease. This study aims to propose the application of a new enhanced recovery after surgery (ERAS) nutritional support regimen in CEA, which can significantly improve the perioperative nutritional status of patients. A total of 74 patients who underwent CEA were included and randomly divided into two groups: 39 patients received nutritional therapy with the ERAS protocol (ERAS group) and 35 patients received routine perioperative nutritional support (control group). Our results showed that the levels of major clinical and biochemical parameters (albumin, hemoglobin, creatinine, calcium and magnesium levels, etc.) in the ERAS group were significantly higher than those in the control group after surgery (p < 0.05). Additionally, patients in the ERAS group had dramatically shorter postoperative length of stay and reflected higher mean satisfaction at discharge (p < 0.001). Moreover, no statistically significant differences were observed in postoperative complication rates and Mini-mental State Examination scores at discharge. The emergence of this neurosurgical ERAS nutritional support program can effectively intervene in perioperative nutritional status, and notably reduce postoperative hospital stays.

Modulation of Intratumoral Fusobacterium nucleatum to Enhance Sonodynamic Therapy for Colorectal Cancer with Reduced Phototoxic Skin Injury.

Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. Fusobacterium nucleatum, a core pathogen of colorectal cancer (CRC), is an important cause of low therapeutic efficacy and metastasis. Thus, the modulation of intratumoral pathogens may provide a target for cancer therapy and metastasis inhibition. Herein, we propose an intratumoral F. nucleatum-modulating strategy for enhancing the therapeutic efficacy of CRC and inhibiting lung metastasis by designing an antibacterial nanoplatform (Au@BSA-CuPpIX), which produced reactive oxygen species (ROS) under ultrasound and exhibited strong antibacterial activity. Importantly, Au@BSA-CuPpIX reduced the levels of apoptosis-inhibiting proteins by inhibiting intratumoral F. nucleatum, thereby enhancing ROS-induced apoptosis. In vivo results demonstrated that Au@BSA-CuPpIX effectively eliminated F. nucleatum to enhance the therapeutic efficacy of sonodynamic therapy (SDT) for orthotopic CRC and inhibit lung metastasis. Notably, entrapped gold nanoparticles reduced the phototoxicity of metalloporphyrin accumulated in the skin during tumor treatment, preventing severe inflammation and damage to the skin. Therefore, this study proposes a strategy for the elimination of F. nucleatum in CRC to enhance the therapeutic effect of SDT, thus providing a promising paradigm for improving cancer treatment with fewer toxic side effects and promoting the clinical translational potential of SDT.

[The Risk and Survival Analysis of Multiple Malignancies in Hematologic Malignancy Patients: A Single Chinese Center Retrospective Study, 2009 through 2017].

OBJECTIVE: To explore the risk and location of multiple malignancies in patients with hematologic malignancies who were followed up for 9 years in Jiangsu Province Hospital and to evaluate the impact of the second primary malignancy on survival of patients. METHODS: The incidence and survival of multiple malignancies in 7 921 patients with hematologic malignancies from 2009 to 2017 were analyzed retrospectively. RESULTS: A total of 180 (2.3%, 180/7 921) patients developed second malignancy, of whom 58 patients were diagnosed with hematologic malignancies as the first primary malignancy, and 98 patients developed hematologic malignancies as second primary malignancy, and the other 24 cases were diagnosed with the second malignancy within 6 months after the first primary malignancy was diagnosed, which was difined as multiple malignancies occurring simultaneously. In 180 patients, 18 cases developed two hematologic malignancies successively, and 11 patients developed more than 3 primary cancers (among them, 2 female patients were diagnosed with 4 primary cancers). Patients with lymphoma and multiple myeloma (MM) as the second primary malignancy had poorer survival than patients with lymphoma and MM as the first primary malignancy. Patients with chronic myeloid leukemia as the second primary malignancy were also associated with inferior overall survival. CONCLUSION: In this study, 2.3% of hematologic malignancy patients had multiple mali-gnancies, lymphoma and MM as the second primary malignancy had poor survival.

Enzyme-catalyzed synthesis of selenium-doped manganese phosphate for synergistic therapy of drug-resistant colorectal cancer.

BACKGROUND: The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. RESULTS: Se-MnP NPs had an organic-inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn2+). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. CONCLUSIONS: OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.

Nodal promotes colorectal cancer survival and metastasis through regulating SCD1-mediated ferroptosis resistance.

Re-expression of an embryonic morphogen, Nodal, has been seen in several types of malignant tumours. By far, studies about Nodal's role in colorectal cancer (CRC) remain limited. Ferroptosis is essential for CRC progression, which is caused by cellular redox imbalance and characterized by lipid peroxidation. Herein, we observed that Nodal enhanced CRC cell's proliferative rate, motility, invasiveness, and epithelial-mesenchymal transition (EMT) in vivo and in vitro. Notably, Nodal overexpression induced monounsaturated fatty acids synthesis and increased the lipid unsaturation level. Nodal knockdown resulted in increased CRC cell lipid peroxidation. Stearoyl-coenzyme A desaturase 1 (SCD1) inhibition at least partially abolished the resistance of Nodal-overexpressing cells to RSL3-induced ferroptosis. Mechanistically, SCD1 was transcriptionally up-regulated by Smad2/3 pathway activation in response to Nodal overexpression. Significant Nodal and SCD1 up-regulation were observed in CRC tissues and were associated with CRC metastasis and poor clinical outcomes. Furthermore, bovine serum albumin nanoparticles/si-Nodal nanocomplexes targeting Nodal had anti-tumour effects on CRC progression and metastasis. This research elucidated the role of Nodal in CRC development and revealed a potential gene-based therapeutic strategy targeting Nodal for improving CRC treatment.

Topoisomerase IIß binding protein 1 serves as a novel prognostic biomarker for stage II-III colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is a commonly diagnosed human malignancy worldwide. Accumulating evidence has suggested DNA repair related proteins widely participate in CRC initiation and development. TOPBP1 is recently identified as a novel regulator for DNA repair, however, its biological role in CRC remains unknown. METHODS: Firstly, the bioinformatics analysis was utilized to investigate the expression and clinical significance of TOPBP1 in CRC patients. Then, a retrospective study enrolling 129 stage II/III CRC patients was performed for validation. The CCK-8, colony formation, transwell assay and xenograft model were used to clarify the biological impact of TOPBP1 on CRC cells. Finally, transcriptome sequencing was performed to investigate the potential oncogenic mechanisms regulated by TOPBP1 in CRC development. RESULTS: The expression of TOPBP1 was significantly higher in CRC tissues than that in normal tissues. High TOPBP1 expression was an independent unfavorable prognostic factor for overall and disease-free survival in II/III CRC patients. Knockdown of TOPBP1 not only significantly inhibited the proliferation, colony formation, invasion, migration and epithelial-mesenchymal transition (EMT) molecular phenotype of CRC cells, while the opposite was for TOPBP1 expression. Moreover, knockdown of TOPBP1 slowed down the growth speed of xenografts. The transcriptome sequencing identified MAP3K3 as a downstream gene of TOPBP1 and MAP3K3 knockdown inhibited the EMT molecular phenotype in CRC cells. Finally, the rescue assay indicated MAP3K3 overexpression counteracted the inhibitory effect of TOPBP1 knockdown on the proliferation, colony formation, invasion, migration and EMT phenotype of CRC cells. CONCLUSION: TOPBP1 promotes the malignant progression of CRC through MAP3K3 induced EMT. TOPBP1 is a promising clinical biomarker or therapeutical target for CRC patients.