Early spiral arteriole remodeling in the uterine-placental interface: A rat model.

The mammalian placenta's interface with the parent is a richly vascularized tissue whose development relies upon communication between many different cell types within the uterine microenvironment. The uterine blood vessels of the interface are reshaped during pregnancy into wide-bore, flaccid vessels that convey parental blood to the exchange region of the placenta. Invasive trophoblast as well as parental uterine macrophages and Natural Killer cells are involved in the stepwise remodeling of these vessels and their respective contributions to this crucial process are still being delineated. However, the earliest steps in arteriole remodeling are understudied as they are difficult to study in humans, and other species lack the deep trophoblast invasion that is so prominent a feature of placentation in humans. Here, we further characterize the rat, with deep hemochorial placentation akin to humans, as a model system in which to tease apart the earliest, relatively understudied events in spiral arteriole remodeling. We show that the rat uterine-placental interface increases in size and vascularity rapidly, before trophoblast invasion. The remodeling stages in the arterioles of the rat uterine-placental interface follow a sequence of anatomical changes similar to those in humans, and there are changes to the arterioles' muscular tunica media prior to the marked influx of immune cells. The rat is a tractable model in which to better understand the cell/cell interactions occurring in vivo in an intact tissue microenvironment over time.

System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening.

OBJECTIVE: Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function. METHODS: In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis. RESULTS: After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma. CONCLUSIONS: Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.

Characteristics, source analysis, and health risk assessment of potentially toxic elements pollution in soil of dense molybdenum tailing ponds area in central China.

The issue of potentially toxic elements (PTEs) contamination of regional soil caused by mining activities and tailings accumulation has attracted wide attention all over the world. The East Qinling is one of the three main molybdenum mines in the world, and the concentration of PTEs such as Hg, Pb and Cu in the slag is high. Quantifying the amount of PTEs contamination in soil and identifying potential sources of contamination is vital for soil environmental management. In the present investigation, the pollution levels of 8 PTEs in the Qinling molybdenum tailings intensive area were quantitatively identified. Additionally, an integrated source-risk method was adopted for resource allocation and risk assessment based on the PMF model, the ecological risk, and the health risk assessment model. The mean concentrations of Cu, Ni, Pb, Cd, Cr, Zn, As, and Hg in the 80 topsoil samples ranged from 0.80 to 13.38 times the corresponding background values; notably high levels were observed for Pb and Hg. The source partitioning results showed that PTEs were mainly affected by four pollution sources: natural and agricultural sources, coal-burning sources, combined transport and mining industry sources, and mining and smelting sources. The health risk assessment results revealed that the risks of soil PTEs for adults are acceptable, while the risks for children exceeded the limit values. The obtained results will help policymakers to obtain the sources of PTEs of tailing ponds intensive area. Moreover, it provides priorities for the governance of subsequent pollution sources and ecological restoration.

A comprehensive assessment of statin discontinuation among patients who concurrently initiate statins and CYP3A4-inhibitor drugs; a multistate transition model.

AIMS: The aim of this study was to describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs. METHODS: A retrospective new-user cohort study design was used to identify (N = 160 828) patients who concurrently initiated CYP3A4 inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104 774) vs. other statins (unexposed to statin DDI, n = 56 054) from the MarketScan commercial claims database (2012-2017). The statin DDI exposed and unexposed groups were matched (2:1) through propensity score matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs vs. those unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities. RESULTS: After concurrently starting stains and CYP3A, patients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4% [95% CI: 71.1, 71.6] vs. 73.3% [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4% [95% CI: 3.3, 3.5] vs. 3.2% [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0% [95% CI: 20.8, 21.3] vs. 19.5% [95% CI: 19.2, 19.8]). ADEs did not change these associations because those exposed to statin DDIs, vs. unexposed, were still less likely to discontinue statin therapy but more likely to discontinue CYP3A4-inhibitor therapy after experiencing an ADE. CONCLUSION: We did not observe any meaningful clinical differences in the probability of premature statin discontinuation between statin users exposed to statin DDIs and those unexposed.

Down-regulation of RCC1 sensitizes immunotherapy by up-regulating PD-L1 via p27kip1 /CDK4 axis in non-small cell lung cancer.

In recent years, although Immune Checkpoint Inhibitors (ICIs) significantly improves survival both in local advanced stage and advanced stage of non-small cell lung cancer (NSCLC), the objective response rate of ICI monotherapy is still only about 20%. Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27kip1 and PD-L1, and decreased the expression level of CDK4 and p-Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD-L1 monoclonal antibody. Therefore, RCC1 could up-regulate the expression level of PD-L1 by regulating p27kip1 /CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD-L1 monoclonal antibody by inhibiting RCC1.

Conditioned generalisation in generalised anxiety disorder: the role of concurrent perceptual and conceptual cues.

Previous research in extinction indicates no difference in US expectancies for aversive and non-aversive unconditioned stimuli (USs). In this study, we bridged these topics by examining how concurrent perceptual and conceptual cues influence conditioned generalisation of generalised anxiety disorder (GAD) patients by using non-aversive USs. The study included two consecutive phases: acquisition and generalisation. In the acquisition phase, we used blue and purple images as the perceptually conditioned stimuli, images of animals and household items as the conceptually conditioned stimuli, and non-aversive images as unconditioned stimuli (US). In the generalisation phase, we used images containing both conceptual and perceptual cues (e.g. blue animals) as the generalisation stimuli. Participants rated the US expectancy for all images. We found that compared with the control group, the patients exhibited generalisation in response to stimuli that included conditional conceptual cues. These results reveal novel evidence of generalisation in GAD and may have implications for considering the concept-based information in extinction treatment.

Wolbachia and Spiroplasma could influence bacterial communities of the spider mite Tetranychus truncatus.

The structures of arthropod bacterial communities are complex. These microbiotas usually provide many beneficial services to their hosts, whereas occasionally they may be parasitical. To date, little is known about the bacterial communities of Tetranychus truncatus and the factors contributing to the structure of its bacterial communities are unexplored yet. Here, we used four symbiont-infected T. truncatus strains-including one Wolbachia and Spiroplasma co-infected strain, two symbiont singly-infected strains and one symbiont uninfected strain-to investigate the influence of endosymbionts on the structure of the host mites' microbiota. Based on 16S rRNA genes sequencing analysis, we found Wolbachia and Spiroplasma were the two most abundant bacteria in T. truncatus and the presence of both symbionts could not change the diversity of bacterial communities (based on alpha-diversity indexes such as ACE, Chao1, Shannon and Simpson diversity index). Symbiont infection did alter the abundance of many other bacterial genera, such as Megamonas and Bacteroides. The structures of bacterial communities differed significantly among symbiont-infected strains. These results suggested a prominent effect of Wolbachia and Spiroplasma on bacterial communities of the host T. truncatus. These findings advance our understanding of T. truncatus microbiota and will be helpful for further study on bacterial communities of spider mites.

Wolbachia dominate Spiroplasma in the co-infected spider mite Tetranychus truncatus.

Wolbachia and Spiroplasma are both maternally inherited endosymbionts in arthropods, and they can co-infect the same species. However, how they interact with each other in the same host is not clear. Here we investigate a co-infected Tetranychus truncatus spider mite strain that shares the same genetic background with singly infected and uninfected strains to detect the impacts of the two symbionts on their host. We found that Wolbachia-infected and Spiroplasma-infected mites can suffer significant fitness costs involving decreased fecundity, although with no effect on lifespan or development. Wolbachia induced incomplete cytoplasmic incompatibility in T. truncatus both in singly infected and doubly infected strains, resulting in female killing. In both females and males of the co-infected spider mite strain, Wolbachia density was higher than Spiroplasma density. Transcriptome analysis of female adults showed that the most differentially expressed genes were found between the co-infected strain and both the singly infected Spiroplasma strain and uninfected strain. The Wolbachia strain had the fewest differentially expressed genes compared with the co-infected strain, consistent with the higher density of Wolbachia in the co-infected strain. Wolbachia, therefore, appears to have a competitive advantage in host mites over Spiroplasma and is likely maintained in populations by cytoplasmic incompatibility despite having deleterious fitness effects.

Estimation of Hub Genes and Infiltrating Immune Cells in Non-Smoking Females with Lung Adenocarcinoma by Integrated Bioinformatic Analysis.

BACKGROUND In recent years, the morbidity and mortality rates of lung adenocarcinoma in non-smoking females have been increasing dramatically. Although much research has been done with some progress, the molecular mechanism remains unclear. In this study we aimed to estimate hub genes and infiltrating immune cells in non-smoking females with lung adenocarcinoma. MATERIAL AND METHODS Firstly, we obtained differentially expressed genes (DEGs) by GEO2R analysis based on 3 independent mRNA microarray datasets of GSE10072, GSE31547, and GSE32863. The DAVID database was utilized for functional enrichment analysis of DEGs. Moreover, we identified hub genes with prognostic value by STRING, Cytoscape, and Kaplan Meier plotter. Subsequently, these genes were further analyzed by Gene Expression Profiling Interactive Analysis, Oncomine, Tumor Immune Estimation Resource, and Human Protein Atlas. Finally, the immune infiltration analysis was performed by CIBERSORT and The Cancer Genome Atlas with R packages. RESULTS We found 315 DEGs enriching in the extracellular matrix organization, cell adhesion, integrin binding, angiogenesis, and hypoxic response. And among these DEGs, we identified 10 hub genes (SPP1, ENG, ATF3, TOP2A, COL1A1, PAICS, CAV1, CAT, TGFBR2, and ANGPT1) of significant prognostic value. Simultaneously, we illustrated the distribution and differential expressions of 22 immune cell subtypes. and dendritic cells resting and macrophages M1 were identified with prognostic significance. CONCLUSIONS The results indicated that 10 hub genes and 2 immune cell subtypes might be promising biomarkers for lung adenocarcinoma in non-smoking females. This finding needs to be further evaluated.

Comprehensive Analysis of Differential Gene Expression to Identify Common Gene Signatures in Multiple Cancers.

BACKGROUND With the development of research on cancer genomics and microenvironment, a new era of oncology focusing on the complicated gene regulation of pan-cancer research and cancer immunotherapy is emerging. This study aimed to identify the common gene expression characteristics of multiple cancers - lung cancer, liver cancer, kidney cancer, cervical cancer, and breast cancer - and the potential therapeutic targets in public databases. MATERIAL AND METHODS Gene expression analysis of GSE42568, GSE19188, GSE121248, GSE63514, and GSE66272 in the GEO database of multitype cancers revealed differentially expressed genes (DEGs). Then, GO analysis, KEGG function, and path enrichment analyses were performed. Hub-genes were identified by using the degree of association of protein interaction networks. Moreover, the expression of hub-genes in cancers was verified, and hub-gene-related survival analysis was conducted. Finally, infiltration levels of tumor immune cells with related genes were explored. RESULTS We found 12 cross DEGs in the 5 databases (screening conditions: "adj p<0.05" and "logFC>2 or logFC<-2"). The biological processes of DEGs were mainly concentrated in cell division, regulation of chromosome segregation, nuclear division, cell cycle checkpoint, and mitotic nuclear division. Furthermore, 10 hub-genes were obtained using Cytoscape: TOP2A, ECT2, RRM2, ANLN, NEK2, ASPM, BUB1B, CDK1, DTL, and PRC1. The high expression levels of the 10 genes were associated with the poor survival of these multiple cancers, as well as ASPM, may be associated with immune cell infiltration. CONCLUSIONS Analysis of the common DEGs of multiple cancers showed that 10 hub-genes, especially ASPM and CDK1, can become potential therapeutic targets. This study can serve as a reference to understand the characteristics of different cancers, design basket clinical trials, and create personalized treatments.

Virtual Surgical Planning for Successful Second-Stage Mandibular Defect Reconstruction Using Vascularized Iliac Crest Bone Flap: A Valid and Reliable Method.

PURPOSE: Second-stage reconstruction of mandibular defects faces problems of anatomic disorder and bone displacement due to tumor resection. As a newer technique, virtual surgical planning (VSP) may help to increase the accuracy and efficiency of the complicated reconstruction. This study aims to evaluate the application of VSP and splint-guided surgery in second-stage mandibular reconstruction using vascularized iliac crest bone flap. METHODS: Between October 2016 and February 2018, 5 patients (3 men and 2 women) with mandibular defects of duration between 8 months and 8 years underwent VSP-aided secondary reconstruction in the School and Hospital of Stomatology of Wuhan University (Wuhan, China). Virtual surgical planning was performed and serial guiding splints were printed to replicate the design into the actual operation. The linear and 3-dimensional deviations after surgery were analyzed. Patient complications and feedback were recorded during follow up. RESULTS: All 5 patients underwent successful reconstruction using vascularized iliac crest bone flap. No serious donor sites or recipient site complications were observed after 10- to 28-month follow-up. In comparison with the presurgery designs, the linear deviations in coronal plane were 2.7 ± 0.4 mm (range, -2.2 to 3.9 mm) in measurements from the condylar head to the condylar head and 0.70 ± 0.6 mm (range, -0.1 to 1.7 mm) from the gonial angle to the gonial angle, and that in sagittal plane was 2.4 ± 0.88 mm (range, -3 to 4.4 mm) from the anterior inferior mandibular border to the center point on the condylar head to the condylar head line. The whole 3-dimensional deviation was 1.2 ± 1.7 mm in all patients. CONCLUSION: Well-designed splints can assist in precise mandibular reconstruction with high efficiency and accuracy, and thus are a reliable method for complicated second-stage mandibular reconstruction. However, to achieve a better outcome, a satisfactory design is required to adapt the complicated and varied defect.

Identification of Saliva Proteins of the Spider Mite Tetranychus evansi by Transcriptome and LC-MS/MS Analyses.

The spider mite Tetranychus evansi has a remarkable ability to suppress and manipulate plant defenses, which makes it an ideal model to investigate plant-herbivores interactions. In this study, a de novo assembly of the transcriptome of T. evansi is performed and the proteins in its secreted saliva by LC-MS/MS are characterized. A total of 29 365 unigenes are assembled and 136 saliva proteins are identified. Comparative analysis of the saliva proteins in T. evansi, T. truncatus, and T. urticae shows that 64 protein groups are shared by at least two Tetranychus species, and 52 protein groups are specifically identified in T. evansi. In addition, some saliva proteins are common in arthropod species, while others are species-specific. These results will help to elucidate the molecular mechanisms by which T. evansi modulates plant defenses.

Phylogenetic signals in pest abundance and distribution range of spider mites.

BACKGROUND: Attributes of pest species like host range are frequently reported as being evolutionarily constrained and showing phylogenetic signal. Because these attributes in turn could influence the abundance and impact of species, phylogenetic information could be useful in predicting the likely status of pests. In this study, we used regional (China) and global datasets to investigate phylogenetic patterns in occurrence patterns and host ranges of spider mites, which constitute a pest group of many cropping systems worldwide. RESULTS: We found significant phylogenetic signal in relative abundance and distribution range both at the regional and global scales. Relative abundance and range size of spider mites were positively correlated with host range, although these correlations became weaker after controlling for phylogeny. CONCLUSIONS: The results suggest that pest impacts are evolutionarily constrained. Information that is easily obtainable - including the number of known hosts and phylogenetic position of the mites - could therefore be useful in predicting future pest risk of species.

Traditional Chinese Medicine Prolongs Progression-Free Survival and Enhances Therapeutic Effects in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)Treated Non-Small-Cell Lung Cancer (NSCLC) Patients Harboring EGFR Mutations.

BACKGROUND Lung cancer is the most common cause of cancer-associated deaths worldwide. This study aimed to investigate the efficacy and safety of Traditional Chinese Medicine combining EGFR-TKIs in treatment of NSCLC patients harboring EGFR mutations. MATERIAL AND METHODS This study involved 153 advanced-stage NSCLC patients harboring EGFR mutations. Patients were divided into a Control group (administered EGFR-TKI, n=61) and an Experimental group (administered Traditional Chinese Medicine combining EGFR and TKI, n=92). Progression-free survival (PFS) was evaluated for exon 19 deletion and/or 21 deletion patients. Disease control rate (DCR) was assessed to observe therapeutic effects. Adverse effects, including rashes, diarrhea, ALT/AST increase, dental ulcers, and onychia lateralis, were also evaluated. RESULTS TCM combining EGFR-TKI (90.11%) demonstrated no DCR improvement compared to single EGFR-TKI (83.33%) (p>0.05). Median PFS (mPFS) of TCM combining EGFR-TKI (13 months) was significantly longer compared to that in the single EGFR-TKI group (8.8 months) (p=0.001). For 19DEL mutant NSCLC, the mPFS (11 months) in TCM combining EGFR-TKI was significantly longer compared to single EGFR-TKI (8.5 months) (p=0.007). The mPFS of L858 mutant NSCLC patients in EGFR-TKI combining CTM (14 months) was significantly longer compared to single EGFR-TKI (9.5 months) (p=0.015). TCM combining EGFR-TKI was more inclined to prolong mPFS of NSCLC with exon 21 deletion. TCM combining EGFR-TKI illustrated no additional adverse effects in NSCLC patients (p=0.956). CONCLUSIONS Application of Traditional Chinese Medicine prolonged progression-free survival and enhanced therapeutic effect in NSCLC patients harboring EGFR mutations receiving EGFR-TKI treatment. Meanwhile, adjunctive Chinese medicine combining EGFR-TKI in NSCLC with EGFR mutations caused no adverse effects.

Incidence of Facultative Bacterial Endosymbionts in Spider Mites Associated with Local Environments and Host Plants.

Spider mites are frequently associated with multiple endosymbionts whose infection patterns often exhibit spatial and temporal variation. However, the association between endosymbiont prevalence and environmental factors remains unclear. Here, we surveyed endosymbionts in natural populations of the spider mite, Tetranychus truncatus, in China, screening 935 spider mites from 21 localities and 12 host plant species. Three facultative endosymbiont lineages, Wolbachia, Cardinium, and Spiroplasma, were detected at different infection frequencies (52.5%, 26.3%, and 8.6%, respectively). Multiple endosymbiont infections were observed in most local populations, and the incidence of individuals with the Wolbachia-Spiroplasma coinfection was higher than expected from the frequency of each infection within a population. Endosymbiont infection frequencies exhibited associations with environmental factors: Wolbachia infection rates increased at localities with higher annual mean temperatures, while Cardinium and Spiroplasma infection rates increased at localities from higher altitudes. Wolbachia was more common in mites from Lycopersicon esculentum and Glycine max compared to those from Zea mays This study highlights that host-endosymbiont interactions may be associated with environmental factors, including climate and other geographically linked factors, as well as the host's food plant.IMPORTANCE The aim of this study was to examine the incidence of endosymbiont distribution and the infection patterns in spider mites. The main findings are that multiple endosymbiont infections were more common than expected and that endosymbiont infection frequencies were associated with environmental factors. This work highlights that host-endosymbiont interactions need to be studied within an environmental and geographic context.

Central nervous system progression in advanced non-small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study.

BACKGROUND: Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis. The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated. METHODS: A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations. Time to neurological progression (nTTP) and median progression-free survival (mPFS) were calculated. RESULTS: The study involved 279 patients (erlotinib group: 108, gefitinib group: 171). After a median follow-up of 22 months, 27 patients (25%) in the erlotinib group and 60 patients (35.1%) in the gefitinib group showed CNS progression. The HR of CNS progression for erlotinib versus gefitinib was 0.695 [95% confidence interval (CI), 0.406-1.190], suggesting a risk reduction of 30.5% although not achieving statistical significance. The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181). However, for those patients with preexisting brain metastases prior to EGFR-TKI treatment, erlotinib as first line treatment significantly extended the median nTTP in comparison to gefitinib (30 months vs 15.8 months, p = 0.024). CONCLUSIONS: Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib. If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.

In vivo photoacoustic flow cytometry-based study of the effect of melanin content on melanoma metastasis.

A major cause of death in cancer patients is distant metastasis of tumors, in which circulating tumor cells (CTCs) are an important marker. Photoacoustic flow cytometry (PAFC) can monitor CTCs in real time, non-invasively, and label-free; we built a PAFC system and validated the feasibility of PAFC for monitoring CTCs using in vivo animal experiments. By cultivating heavily-pigmented and moderately-pigmented melanoma cells, more CTCs were detected in mice inoculated with moderately-pigmented tumor cells, resulting in more distant metastases and poorer survival status. Tumor cells with lower melanin content may produce more CTCs, increasing the risk of metastasis. CTC melanin content may be down-regulated during the metastatic which may be a potential indicator for assessing the risk of melanoma metastasis. In conclusion, PAFC can be used to assess the risk of melanoma metastasis by dynamically monitoring the number of CTCs and the CTC melanin content in future clinical diagnoses.

Preclinical Advances in LNP-CRISPR Therapeutics for Solid Tumor Treatment.

Solid tumors, with their intricate cellular architecture and genetic heterogeneity, have long posed therapeutic challenges. The advent of the CRISPR genome editing system offers a promising, precise genetic intervention. However, the journey from bench to bedside is fraught with hurdles, chief among them being the efficient delivery of CRISPR components to tumor cells. Lipid nanoparticles (LNPs) have emerged as a potential solution. This biocompatible nanomaterial can encapsulate the CRISPR/Cas9 system, ensuring targeted delivery while mitigating off-target effects. Pre-clinical investigations underscore the efficacy of LNP-mediated CRISPR delivery, with marked disruption of oncogenic pathways and subsequent tumor regression. Overall, CRISPR/Cas9 technology, when combined with LNPs, presents a groundbreaking approach to cancer therapy, offering precision, efficacy, and potential solutions to current limitations. While further research and clinical testing are required, the future of personalized cancer treatment based on CRISPR/Cas9 holds immense promise.

Sacubitril/valsartan can improve the cardiac function in heart failure patients with a history of cancer: An observational study.

Sacubitril/Valsartan, the combination of angiotensin receptor inhibitor and neprilysin inhibitor, is now becoming the class 1 recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. By searching the patients with a diagnosis of both cancer and Heart failure (HF) over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (P < .05) and better NYHA function classification after the treatment. We also observed fewer cases of deterioration on LAD (P = .029) and LVEDD (P = .023) in Sacubitril/Valsartan group. In subgroup analysis, our study showed that all 3 kinds of HF patients had better LVEF, LVFS, and NT-proBNP in Sacubitril/Valsartan group (P < .05). Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all 3 kinds of HF. This is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of 3 kinds of HF.

Cone-wedge anchored surgical templates for stackable metal guide: a novel technique.

OBJECTIVE: To address the instability in implant surgical guides, this technique proposes an alternative anchoring mechanism in the stackable metal surgical guides utilizing cone-wedge anchors for improved stability. METHODS: Postoperative implant position superimposed onto the preoperatively planned design using Mimics Medical 21.0 and Materialise Magics 24.0 to assess 3D coronal implant deviation, 3D apical implant deviation, and implant angular deviation. RESULTS: Postoperative cone-beam computed tomography (CBCT) revealed a high level of precision in the implant placement, with an average 0.97 mm deviation at implant coronal region, 1.56 mm at implant apexes, and 2.95° angular deviation. CONCLUSION: This technique introduces a novel cone-wedge anchoring mechanism to enhance the stability of stackable metal surgical guide templates, addressing inherent instability issues. The utilization of this approach significantly improves the accuracy of implant placement procedures.