Downregulating miRNA-199a-5p exacerbates fluorouracil-induced cardiotoxicity by activating the ATF6 signaling pathway.

BACKGROUND: Fluorouracil (5-FU) might produce serious cardiac toxic reactions. miRNA-199a-5p is a miRNA primarily expressed in myocardial cells and has a protective effect on vascular endothelium. Under hypoxia stress, the expression level of miRNA-199a-5p was significantly downregulated and is closely related to cardiovascular events such as coronary heart disease, heart failure, and hypertension. We explored whether 5-FU activates the endoplasmic reticulum stress ATF6 pathway by regulating the expression of miRNA-199a-5p in cardiac toxicity. METHODS: This project established a model of primary cardiomyocytes derived from neonatal rats and treated them with 5-FU in vitro. The expression of miRNA-199a-5p and its regulation were explored in vitro and in vivo. RESULTS: 5-FU decreases the expression of miRNA-199a-5p in cardiomyocytes, activates the endoplasmic reticulum stress ATF6 pathway, and increases the expression of GRP78 and ATF6, affecting the function of cardiomyocytes, and induces cardiac toxicity. The rescue assay further confirmed that miRNA-199a-5p supplementation can reduce the cardiotoxicity caused by 5-FU, and its protective effect on cardiomyocytes depends on the downregulation of the endoplasmic reticulum ATF6 signaling pathway. CONCLUSIONS: 5-FU can down-regulate expression of miRNA-199a-5p, then activate the endoplasmic reticulum stress ATF6 pathway, increase the expression of GRP78 and ATF6, affect the function of cardiomyocytes, and induce cardiac toxicity.

Analysis of the Relationship between Scleritis and T Cell Activation in Patients with Hepatocellular Carcinoma Treated with PD-1 Carrelizumab.

In order to explore the function of inhibiting the immune effect, the relationship between programmed death receptor 1 (PD-1) carrelizumab in the treatment of hepatocellular carcinoma-induced scleritis and T cell activation is investigated. A total of 120 patients with primary liver cancer treated in the department of oncology of our hospital from July 2020 to January 2022 are selected and treated with carrelizumab. According to the occurrence of PD-1 carrelizumab treatment, the patients are divided into the scleritis group and nonscleritis group. The levels of T cells, PD-1, PD-L1 proteins, and serum inflammatory factors at different time points are compared. The experimental results show that the occurrence of scleritis after liver cancer treatment with PD-1 carrelizumab is closely associated with Treg cells, the percentage of Th17 cells, the expression of PD-1, PD-L1 proteins, and inflammatory factors. It is clearly evident that PD-1 carrelizumab can increase the risk of scleritis by affecting T cell activation.

Effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization in primary liver cancer patients.

OBJECTIVE: The study aimed to explore the effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization on the immune function of primary liver cancer patients. METHODS: The study included 84 primary liver cancer patients who received treatment at our hospital between April 2018 and January 2020. They were divided into the control group (n=42, hepatic artery chemoembolization) and the study group (n=42, image-guided adaptive radiotherapy combined with hepatic artery chemoembolization) using the random number table method. AFP, ALT, AST, CA724, CA242 and immune function before and after treatment were compared in the two groups and the short-term efficacy and adverse events (AEs) were statistically analyzed. The two groups were followed up. RESULTS: After treatment, the study group had a higher ORR and DCR compared to the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of AFP, ALT, AST, CA724 and CA242 between the two groups before treatment (P > 05). After treatment, the study group had lower levels of AFP, ALT, AST, CA724 and CA242 than the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of CD4+, CD8+, and CD4+/CD8+ before treatment in the two groups (P > 05). After treatment, the study group had higher levels of CD4+ and CD4+/CD8+ but lower levels of CD8+ compared to the control group, and the difference was statistically significant (P < 0.05). In the study group, 2 patients developed radiation-induced liver disease, and the incidence was 4.76% (2/42), which occurred at 4 and 6 weeks after the end of radiotherapy, respectively. The patients mainly had elevated transaminases, ascites, and liver enlargement and hepatoprotection and nutritional support were provided, and the patients gradually recovered after treatment. There was no statistical difference in the incidence of AEs between the two groups (p > 0.05). All patients in the study completed follow up and the follow up completion rate was 100%. The median duration of follow up was 22.5 months. In the study group, 12 of 42 patients (28.57%) died and 21 cases (50.00%) had recurrence. In the control group, 21 of 42 cases (50.00%) died and 27 cases (64.29%) recurred. At 1 year, there was no statistical difference in ORR and DCR between the two groups (P > 0.05) and at 2 years, the study group had a higher ORR and DCR than the control group, and the difference was statistically significant (P < 0.05). CONCLUSION: Image-guided adaptive radiotherapy combined with hepatic artery chemoembolization may improve the immune function of primary liver cancer patients and is of important clinical application value.

Effect of camrelizumab plus transarterial chemoembolization on massive hepatocellular carcinoma.

OBJECTIVE: To investigate the efficacy of camrelizumab plus transarterial chemoembolization (TACE) on massive hepatocellular carcinoma (HCC) patients. METHODS: A total of 92 cases with massive HCC from October 2019 to January 2021 were prospectively enrolled and randomly divided into the study group (n = 46) and the control group (n = 46). The control group received TACE while the study group were treated with camrelizumab plus TACE. The primary end points were clinical efficacy and adverse events. And the secondary end points were liver function, and alpha fetoprotein (AFP), carcino-embryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) levels before and after treatment. RESULTS: All participants were followed-up for 7 to 24 months, with a median of 12 months. Patients in the study group received TACE for 1-3 times, with an average of (2.01 ± 0.09) times, while patients in the control group receive TACE for 2-4 times, with an average of (3.78 ± 0.12) times, and the control group received significantly more TACEs (χ2 = 5.518, P = 0.019). During the follow-up, the response rate and disease control rate of the study group were significantly higher than those of the control group (χ2 = 5.518, P = 0.019; χ2 = 4.467, P = 0.041). Before treatment, the levels of total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alpha-fetoprotein (AFP), CEA, and CA19-9 were comparable between the groups (P > 0.05). After treatment, the levels of TBIL, ALT, AST, AFP, CEA, and CA19-9 decreased, and the above indicators in the study group were significantly lower than those in the control group (P < 0.05). All patients showed transient liver damage, vomiting, nausea, fever and abdominal pain after surgery, and their symptoms were relieved after symptomatic treatment. Adverse events occurred in 9 cases in the study group, and 3 cases in the control group (χ2 = 3.419, P = 0.064). CONCLUSION: Compared with TACE alone, camrelizumab plus TACE treatment can significantly improve the liver function of patients with massive HCC and enhance the treatment effect, which is worthy of clinical promotion.

Multiple Kernel Clustering With Neighbor-Kernel Subspace Segmentation.

Multiple kernel clustering (MKC) has been intensively studied during the last few decades. Even though they demonstrate promising clustering performance in various applications, existing MKC algorithms do not sufficiently consider the intrinsic neighborhood structure among base kernels, which could adversely affect the clustering performance. In this paper, we propose a simple yet effective neighbor-kernel-based MKC algorithm to address this issue. Specifically, we first define a neighbor kernel, which can be utilized to preserve the block diagonal structure and strengthen the robustness against noise and outliers among base kernels. After that, we linearly combine these base neighbor kernels to extract a consensus affinity matrix through an exact-rank-constrained subspace segmentation. The naturally possessed block diagonal structure of neighbor kernels better serves the subsequent subspace segmentation, and in turn, the extracted shared structure is further refined through subspace segmentation based on the combined neighbor kernels. In this manner, the above two learning processes can be seamlessly coupled and negotiate with each other to achieve better clustering. Furthermore, we carefully design an efficient iterative optimization algorithm with proven convergence to address the resultant optimization problem. As a by-product, we reveal an interesting insight into the exact-rank constraint in ridge regression by careful theoretical analysis: it back-projects the solution of the unconstrained counterpart to its principal components. Comprehensive experiments have been conducted on several benchmark data sets, and the results demonstrate the effectiveness of the proposed algorithm.

Efficacy and safety of taxane-based systemic chemotherapy of advanced gastric cancer: A systematic review and meta-analysis.

Taxanes are chemotherapeutic agents commonly used to treat several cancers. However, the effects of taxanes on advanced gastric cancer (AGC) are still not clear, especially when used as a first-line treatment. This systematic review and meta-analysis aims to investigate the efficacy and safety of taxanes as a first-line treatment of AGC. The quality of our included studies was assessed using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs, and the data of the included studies was of satisfactory quality to analyze. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity. Taxanes significantly improved OS (HR = 0.84, 95% CI 0.76-0.92, P = 0.0004) and had a slight effect on ORR (RR = 1.23, 95% CI 1.00-1.51, P = 0.05). However, taxanes may also increase the risks of neutropenia and leucopenia, similar to effects observed in other conventional chemotherapeutic treatments such as oxaliplatin and epirubicin. Therefore, patient characteristics including concomitant diseases, physical condition, and prior therapies should be considered before selecting taxane-based treatments for AGC.

Mechanism of immune evasion in breast cancer.

Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body's immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

Intraoperative radiotherapy in gastric and esophageal cancer: meta-analysis of long-term outcomes and complications.

INTRODUCTION: The treatment effects of intraoperative radiotherapy (IORT) for gastric and esophageal cancer remain uncertain. We therefore performed meta-analyses to investigate whether IORT was associated with more favorable oncologic outcomes when compared to non-IORT for patients who have gastric or esophageal cancer. EVIDENCE ACQUISITION: PubMed, Embase, and the references of relevant studies were systematically searched up to March 2016. Outcomes were analyzed with fixed-effect or random-effect models, and the meta-analysis was completed with odds ratio (OR), hazards ratio (HR), and 95% confidence intervals (CI) as effect values. EVIDENCE SYNTHESIS: Eleven studies were included, nine for gastric cancer and two for esophageal cancer. The studies included 1581 patients, 570 in the IORT group and 1011 in the control group. There was no significant difference in overall survival (OS) between the IORT group and control group (HR=0.91, 95% CI: 0.73-1.13; P=0.38). Two subgroups based on cancer type also had the similar results (gastric group: HR=0.98, 95% CI: 0.78-1.24, P=0.87; esophagus group: HR=0.63, 95% CI: 0.37-1.05, P=0.08). Besides, IORT showed favorable effects for patients with cancer in stage II and stage III and had the advantage of loco-regional control. Regarding the complications, the occurrence rate had no significant difference between the IORT group and control group (OR=1.15; 95% CI: 0.77-1.72; P=0.50). CONCLUSIONS: According to our meta-analysis, IORT did not extend the OS in gastric cancer and esophageal cancer patients, but had a favorable effect for specific stage patients to show loco-regional control, and did not increase the risk of complications.

Transanal total mesorectal excision (taTME) for rectal cancer: a systematic review and meta-analysis of oncological and perioperative outcomes compared with laparoscopic total mesorectal excision.

BACKGROUND: Transanal total mesorectal excision (taTME) is an emerging surgical technique for rectal cancer. However, the oncological and perioperative outcomes are controversial when compared with conventional laparoscopic total mesorectal excision (laTME). METHODS: A systematic review and meta-analysis based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted in PubMed, Embase and Cochrane database. All original studies published in English that compared taTME with laTME were included for critical appraisal and meta-analysis. Data synthesis and statistical analysis were carried out using RevMan 5.3 software. RESULTS: A total of seven studies including 573 patients (taTME group = 270; laTME group = 303) were included in our meta-analysis. Concerning the oncological outcomes, no differences were observed in harvested lymph nodes, distal resection margin (DRM) and positive DRM between the two groups. However, the taTME group showed a higher rate of achievement of complete grading of mesorectal quality (OR = 1.75, 95% CI = 1.02-3.01, P = 0.04), a longer circumferential resection margin (CRM) and less involvement of positive CRM (CRM: WMD = 0.96, 95% CI = 0.60-1.31, P <0.01; positive CRM: OR = 0.39, 95% CI = 0.17-0.86, P = 0.02). Concerning the perioperative outcomes, the results for hospital stay, intraoperative complications and readmission were comparable between the two groups. However, the taTME group showed shorter operation times (WMD = -23.45, 95% CI = -37.43 to -9.46, P <0.01), a lower rate of conversion (OR = 0.29, 95% CI = 0.11-0.81, P = 0.02) and a higher rate of mobilization of the splenic flexure (OR = 2.34, 95% CI = 0.99-5.54, P = 0.05). Although the incidence of anastomotic leakage, ileus and urinary morbidity showed no difference between the groups, a significantly lower rate of overall postoperative complications (OR = 0.65, 95% CI = 0.45-0.95, P = 0.03) was observed in the taTME group. CONCLUSIONS: In comparison with laTME, taTME seems to achieve comparable technical success with acceptable oncologic and perioperative outcomes. However, multicenter randomized controlled trials are required to further evaluate the efficacy and safety of taTME.

A dose-response meta-analysis reveals an association between vitamin B12 and colorectal cancer risk.

OBJECTIVE: The current meta-analysis evaluated the association between vitamin B12 intake and blood vitamin B12 level and colorectal cancer (CRC) risk. DESIGN: The PubMed and EMBASE databases were searched. A dose-response analysis was performed with generalized least squares regression, with the relative risk (RR) and 95 % CI as effect values. SETTING: The meta-analysis included seventeen studies. SUBJECTS: A total of 10 601 patients. RESULTS: The non-linear dose-response relationship between total vitamin B12 intake and CRC risk was insignificant (P=0·690), but the relationship between dietary vitamin B12 intake and CRC risk was significant (P<0·001). Every 4·5 µg/d increment in total and dietary vitamin B12 intake was inversely associated with CRC risk (total intake: RR=0·963; 95 % CI 0·928, 0·999; dietary intake: RR=0·914; 95 % CI 0·856, 0·977). The inverse association between vitamin B12 intake and CRC risk was also significant when vitamin B12 intake was over a dosage threshold, enhancing the non-linear relationship. The non-linear dose-response relationship between blood vitamin B12 level and CRC risk was insignificant (P=0·219). There was an insignificant association between every 150 pmol/l increment in blood vitamin B12 level and CRC risk (RR=1·023; 95 % CI 0·881, 1·187). CONCLUSIONS: Our meta-analysis indicates that evidence supports the use of vitamin B12 for cancer prevention, especially among populations with high-dose vitamin B12 intake, and that the association between CRC risk and total vitamin B12 intake is stronger than between CRC risk and dietary vitamin B12 intake only.

Hybrid epidemics--a case study on computer worm conficker.

Conficker is a computer worm that erupted on the Internet in 2008. It is unique in combining three different spreading strategies: local probing, neighbourhood probing, and global probing. We propose a mathematical model that combines three modes of spreading: local, neighbourhood, and global, to capture the worm's spreading behaviour. The parameters of the model are inferred directly from network data obtained during the first day of the Conficker epidemic. The model is then used to explore the tradeoff between spreading modes in determining the worm's effectiveness. Our results show that the Conficker epidemic is an example of a critically hybrid epidemic, in which the different modes of spreading in isolation do not lead to successful epidemics. Such hybrid spreading strategies may be used beneficially to provide the most effective strategies for promulgating information across a large population. When used maliciously, however, they can present a dangerous challenge to current internet security protocols.

Optimizing hybrid spreading in metapopulations.

Epidemic spreading phenomena are ubiquitous in nature and society. Examples include the spreading of diseases, information, and computer viruses. Epidemics can spread by local spreading, where infected nodes can only infect a limited set of direct target nodes and global spreading, where an infected node can infect every other node. In reality, many epidemics spread using a hybrid mixture of both types of spreading. In this study we develop a theoretical framework for studying hybrid epidemics, and examine the optimum balance between spreading mechanisms in terms of achieving the maximum outbreak size. We show the existence of critically hybrid epidemics where neither spreading mechanism alone can cause a noticeable spread but a combination of the two spreading mechanisms would produce an enormous outbreak. Our results provide new strategies for maximising beneficial epidemics and estimating the worst outcome of damaging hybrid epidemics.

Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection.

HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

Structural and compositional evolution of FePt nanocubes in oganometallic synthesis.

In this study, the mechanisms for the formation of FePt nanocubes via pyrolysis of iron pentacarbonate [Fe(CO)5] and platinum(II) acetylacetonate [Pt(acac)2] were investigated. The time evolution of the structure, morphology, and composition of the FePt nanocubes was probed by transmission electron microscopy (TEM) at different reaction stages. On the basis of the detailed characterization, we determined the following aspects of the reaction mechanism: (1) The FePt nanocubes are rapidly formed at 160°C to 180°C by the decomposition of the precursors, and the formation of the FePt nanocubes is dominated by the nucleation of Pt-rich species followed by a slow deposition process of Fe atoms. (2) A thin Fe atomic layer is present on the FePt nanocubes, which does not influence their phase transition into a fct structure. (3) The use of Fe(CO)5 is the key factor leading to the anisotropic growth of the FePt nanocubes, and the Fe(CO)5/Pt(acac)2 molar ratio not only determines the composition of the resulting FePt nanocubes but also affects their morphology and structures.