Regulation of tumor antigens-Dependent immunotherapy via the hybrid M1 macrophage/tumor lysates Hydrogel.

Tumor treatment poses a significant obstacle in contemporary healthcare. Using components derived from a patient's own cellular and tissue materials to prepare hydrogels and other therapeutic systems has become a novel therapeutic approach, drawing considerable interest for their applicability in basic research on cancer immunotherapy. These hydrogels can engage with cellular components directly and offer a supportive scaffold, aiding in the normalization of tumor tissues. Additionally, their superior capability for encapsulating targeted anti-tumor medications amplifies treatment effectiveness. Given their origin from a patient's own cells, these hydrogels circumvent the risks of immune rejection by the body and severe side effects typically associated with foreign substance. In this study, we developed a composite hydrogel constructed by the cellular lysates of autologous tumor cells and M1 macrophages. This combination promoted the M2 macrophages polarization to the M1 phenotype. Subsequently, the polarized M1 macrophages infiltrated into the hydrogel and can directly capture tumor antigens. As antigen-presenting cells, M1 macrophages can stimulate the production of antigen-specific T cells to kill tumor cells. This work proposes a dual-benefit research strategy that not only polarizes M2 macrophages but also enhances immune activation, boosting T cell-mediated tumor-killing effects. This approach offers a new therapeutic option for clinical cancer immunotherapy.

Human Amniotic Epithelial Stem Cells Alleviate Autoimmune Premature Ovarian Insufficiency in Mice by Targeting Granulosa Cells via AKT/ERK Pathways.

Autoimmune factors play an important role in premature ovarian insufficiency (POI). Human amniotic epithelial stem cells (hAESCs) have recently shown promising treatment effects on chemotherapy-induced POI. However, the therapeutic efficacy and underlying mechanisms of hAESCs in autoimmune POI remain to be investigated. In this study, we showed for the first time that intravenous transplantation of hAESCs could reside in the ovary of zona pellucida 3 peptide (pZP3) induced autoimmune POI mice model for at least 4 weeks. hAESCs could improve ovarian function and fertility, alleviate inflammation and reduce apoptosis of granulosa cells (GCs) in autoimmune POI mice. The transcriptome analysis of mice ovaries and in vitro co-cultivation experiments suggest that activation of the AKT and ERK pathways may be the key mechanism in the therapeutic effect of hAESCs. Our work provides the theoretical and experimental foundation for optimizing the administration of hAESCs, as well as the clinical application of hAESCs in autoimmune POI patients.

Identification and Validation of SLC9A2 as A Potential Tumor Suppressor in Colorectal Cancer: Integrating Bioinformatics Analysis with Experimental Confirmation.

OBJECTIVE: To uncover the mechanisms underlying the development of colorectal cancer (CRC), we applied bioinformatic analyses to identify key genes and experimentally validated their possible roles in CRC onset and progression. METHODS: We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on differentially expressed genes (DEGs), constructed a protein-protein interaction (PPI) network to find the top 10 hub genes, and analyzed their expression in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). We also studied the correlation between these genes and immune cell infiltration and prognosis and validated the expression of SLC9A2 in CRC tissues and cell lines using qRT-PCR and Western blotting. Functional experiments were conducted in vitro to investigate the effects of SLC9A2 on tumor growth and metastasis. RESULTS: We found 130 DEGs, with 45 up-regulated and 85 down-regulated in CRC. GO analysis indicated that these DEGs were primarily enriched in functions related to the regulation of cellular pH, zymogen granules, and transmembrane transporter activity. KEGG pathway analysis revealed that the DEGs played pivotal roles in pancreatic secretion, rheumatoid arthritis, and the IL-17 signaling pathway. We identified 10 hub genes: CXCL1, SLC26A3, CXCL2, MMP7, MMP1, SLC9A2, SLC4A4, CLCA1, CLCA4, and ZG16. GO enrichment analysis showed that these hub genes were predominantly involved in the positive regulation of transcription. Gene expression analysis revealed that CXCL1, CXCL2, MMP1, and MMP7 were highly expressed in CRC, whereas CLCA1, CLCA4, SLC4A4, SLC9A2, SLC26A3, and ZG16 were expressed at lower levels. Survival analysis revealed that 5 key genes were significantly associated with the prognosis of CRC. Both mRNA and protein expression levels of SLC9A2 were markedly reduced in CRC tissues and cell lines. Importantly, SLC9A2 overexpression in SW480 cells led to a notable inhibition of cell proliferation, migration, and invasion. Western blotting analysis revealed that the expression levels of phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) proteins were significantly increased, whereas there were no significant changes in the expression levels of ERK and JNK following SLC9A2 overexpression. Correlation analysis indicated a potential link between SLC9A2 expression and the MAPK signaling pathway. CONCLUSION: Our study suggests that SLC9A2 acts as a tumor suppressor through the MAPK pathway and could be a potential target for CRC diagnosis and therapy.

Amphiphilic hydroxyethyl starch-based nanoparticles carrying linoleic acid modified berberine inhibit the expression of krasv12 oncogene in zebrafish.

Cancer is one of the most lethal diseases all over the world. Despite that many drugs have been developed for cancer therapy, they still suffer from various limitations including poor treating efficacy, toxicity to normal human cells, and the emergence of multidrug resistance. In this study, the amphiphilic LHES polymers were prepared using hydroxyethyl starch (HES) and linoleic acid as starting materials. The content and substitution degree of linoleic acid groups in LHES polymers were analyzed. The LHES polymers were used for fabricating LHES-B nanoparticles carrying a linoleic acid modified berberine derivative (L-BBR). The LHES-B nanoparticles showed high drug loading efficiency (29%) and could quickly release L-BBR under acidic pH condition (pH = 4.5). Biological investigations revealed that LHES-B nanoparticles significantly inhibited the proliferation of HepG2 cells and exhibited higher cytotoxicity than L-BBR. In a transgenic Tg(fabp10:rtTA2s-M2; TRE2:EGFP-krasv12) zebrafish model, LHES-B nanoparticles obviously inhibited the expression of krasv12 oncogene. These results indicated that LHES carriers could improve the anticancer activity of L-BBR, and the synthesized LHES-B nanoparticles showed great potential as anticancer drug.

Precise capture of circulating endometrial cells in endometriosis.

BACKGROUND: Endometriosis (EM) is a complex benign gynecological disease, but it has malignant biological behavior and can invade any part of the body. Clinical manifestations include pelvic pain, dysmenorrhea, infertility, pelvic nodules, and masses. Our previous study successfully detected circulating endometrial cells (CECs) in the peripheral blood of patients with EM. The purpose of this study is to overcome the limitation of cell size in the previous microfluidic chip method, to further accurately capture CECs, understand the characteristics of these cells, and explore the relationship between CECs and the clinical course characteristics of patients with EM. METHODS: Human peripheral venous blood used to detect CECs and circulating vascular endothelial cells (CVECs) was taken from EM patients ( n = 34) hospitalized in the Peking University People's Hospital. We used the subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) method to exclude the interference of red blood cells, white blood cells, and CVECs, so as to accurately capture the CECs in the peripheral blood of patients with EM. Then we clarified the size and ploidy number of chromosome 8 of CECs, and a second grouping of patients was performed based on clinical characteristics to determine the relationship between CECs and clinical course characteristics. RESULTS: The peripheral blood of 34 EM patients and 12 non-EM patients was evaluated by SE-iFISH. Overall, 34 eligible EM patients were enrolled. The results showed that the detection rates of CECs were 58.8% in EM patients and 16.7% in the control group. However, after classification according to clinical characteristics, more CECs could be detected in the peripheral blood of patients with rapidly progressive EM, with a detection rate of 94.4% (17/18). In total, 63.5% (40/63) of these cells were small cells with diameters below 5 µm, and 44.4% (28/63) were aneuploid cells. No significant association was found between the number of CECs and EM stage. CONCLUSION: The number and characteristics of CECs are related to the clinical course characteristics of patients with EM, such as pain and changes in lesion size, and may be used as biomarkers for personalized treatment and management of EM in the future.

Conventional dendritic cells 2, the targeted antigen-presenting-cell, induces enhanced type 1 immune responses in mice immunized with CVC1302 in oil formulation.

Multifunctional CD4+ T helper 1 (Th1) cells, producing IFN-γ, TNF-α and IL-2, define a correlate of vaccine-mediated protection against intracellular infection. In our previous study, we found that CVC1302 in oil formulation promoted the differentiation of IFN-γ+/TNF-α+/IL-2+Th1 cells. In order to extend the application of CVC1302 in oil formulation, this study aimed to elucidate the mechanism of action in improving the Th1 immune response. Considering the signals required for the differentiation of CD4+ T cells to Th1 cells, we detected the distribution of innate immune cells and the model antigen OVA-FITC in lymph node (LN), as well as the quantity of cytokines produced by the innate immune cells. The results of these experiments show that, cDC2 and OVA-FITC localized to interfollicular region (IFR) of the draining lymph nodes, inflammatory monocytes localized to both IFR and T cell zone, which mainly infiltrate from the blood. In this inflammatory niche within LN, CD4+ T cells were attracted into IFR by CXCL10, secreted by inflammatory monocytes, then activated by cDC2, secreting IL-12. Above all, CVC1302 in oil formulation, on the one hand, targeted antigen and inflammatory monocytes into the LN IFR in order to attract CD4+ T cells, on the other hand, targeted cDC2 to produce IL-12 in order to promote optimal Th1 differentiation. The new finding will provide a blueprint for application of immunopotentiators in optimal formulations.

Retracted: Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Wei Wei, Yanqin Wang, Xiaoming Yu, Lan Ye, Yuhua Jiang, Yufeng Cheng. Expression of TP53, BCL-2, and VEGFA Genes in Esophagus Carcinoma and its Biological Significance. Med Sci Monit, 2015; 21: 3016-3022. DOI: 10.12659/MSM.894640.

Efficacy and safety of platelet-rich plasma combined with Tai Chi for knee osteoarthritis: study protocol for a placebo-controlled randomized trial.

BACKGROUND: No definitive treatment methods of curative for knee osteoarthritis (KOA). The combined therapies that into account both the biochemical and biomechanical may provide potential opportunities for treat KOA, and previous studies have demonstrated that the platelet-rich plasma of intra-articular injection (IAI-PRP) and exercise treatments afford more benefits than do their corresponding monotherapies. The absence of a specific exercise plan and detailed explanation renders the aforementioned study results questionable. Furthermore, Tai Chi (TC) with moderate-intensity, whole body movements and good adherence may prove to be more effective for treating KOA. However, few studies examined the effectiveness and safety of combined IAI-PRP and TC for KOA. METHODS: This study protocol will be a placebo-controlled, assessor-blinded randomized trial involving 12-week intervention and 1-year follow-up. The stratified randomization will be used to randomly assign the 212 participants to four groups: group A (placebo IAI); group B (PRP IAI); group C (TC and placebo IAI); group D (TC and PRP IAI). Injection will be performed once a week, three consecutive times as a course, after a week of rest to continue the next course, a total of 3 courses (12 week). Additionally, the TC interventions will be carried out 3 days per week for a total of 12 weeks. The primary outcome measures will include the efficacy (Western Ontario and McMaster Universities Osteoarthritis Index), acceptability and safety of these interventions. The secondary outcome measures will include physical function (Timed Up and Go test), walking function (Gait Analysis), inflammatory factor levels (e.g., Interleukin-1 ß, interleukin-6, vascular endothelial growth factor), quality of life (36-Item Short Form Health Survey), volume of patellofemoral cartilage and effusion-synovitis (MRI). Two-way of variance with repeated measures will be applied to examine the main effects of the group and the time factor and group-time interaction effects for all outcome measures. DISCUSSION: This trial will be first one to propose an integrated scheme combing IAI-PRP and TC for treatment of KOA, based on the consideration of the biochemical and biomechanical pathogenesis of KOA. These results of the study will provide evidence with high quality for integrated IAI-PRP and TC to treatment KOA. Trial Registration Chinese Clinical Trial Registry ChiCTR2300067559. Registered on 11 January 2023.

Leucine-rich glioma-inactivated protein 1 antibody-associated encephalitis in a 22-month-old girl: a case report.

BACKGROUND: LGI-1 antibody-associated encephalitis is a type of autoimmune encephalitis with a lower prevalence than NMDAR antibody-associated encephalitis. LGI-1 antibody-associated encephalitis is the second most prevalent of all autoimmune encephalitides. LGI-1 antibodies interfere with the interactions of inter-synaptic proteins to produce clinical manifestations (N Engl J Med 378:840-851, 2018). CASE PRESENTATION: Leucine-rich glioma-inactivated protein 1 (LGI-1) antibody-associated encephalitis is a subtype of autoimmune encephalitis with a low incidence. We report a case of a girl aged 22 months with convulsive seizures, psycho-behavioral abnormalities, sleep disorders, and limb tremors. This patient was diagnosed with LGI-1 antibody-associated encephalitis based on electroencephalography (EEG) examinations and autoimmune encephalitis antibody analyses. A combined therapy of anti-epileptic and immunosuppressant drugs was effective in controlling the patient's neurological symptoms. CONCLUSIONS: The incidence of LGI-1 antibody-associated encephalitis is low and it occurs mostly in middle-aged and elderly patients, although it occasionally occurs in pediatric patients. To the best of our knowledge, this report describes the youngest patient with LGI-1 antibody-associated encephalitis. Following timely diagnosis, administration of anti-epileptic and immunosuppressant therapy was remarkably effective.

Long-term detraining reverses the improvement of lifelong exercise on skeletal muscle ferroptosis and inflammation in aging rats: fiber-type dependence of the Keap1/Nrf2 pathway.

We investigated the effects of lifelong aerobic exercise and 8 months of detraining after 10 months of aerobic training on circulation, skeletal muscle oxidative stress, and inflammation in aging rats. Sprague-Dawley rats were randomly assigned to the control (CON), detraining (DET), and lifelong aerobic training (LAT) groups. The DET and LAT groups began aerobic treadmill exercise at the age of 8 months and stopped training at the 18th and 26th month, respectively; all rats were sacrificed when aged 26 months. Compared with CON, LAT remarkably decreased serum and aged skeletal muscle 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Superoxide dismutase 2(SOD2) levels were higher in the LAT group than in the CON group in skeletal muscle. However, DET remarkably decreased SOD2 protein expression and content in the skeletal muscle and increased malondialdehyde (MDA) level compared with LAT. Compared with LAT, DET remarkably downregulated adiponectin and upregulated tumor necrosis factor alpha (TNF-α) expression, while phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and 70-kDa ribosomal protein S6 kinase (P70S6K) protein expression decreased, and that of FoxO1 and muscle atrophy F-box (MAFbX) proteins increased in the quadriceps femoris. Adiponectin and TNF-α expression in the soleus muscle did not change between groups, whereas that of AKT, mammalian target of rapamycin (mTOR), and P70S6K was lower in the soleus in the DET group than in that in the LAT group. Compared with that in the LAT group, sestrin1 (SES1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the DET group was lower, whereas Keap1 mRNA expression was remarkably upregulated in the quadriceps femoris. Interestingly, the protein and mRNA levels of SES1, Nrf2, and Keap1 in soleus muscle did not differ between groups. LAT remarkably upregulated ferritin heavy polypeptide 1(FTH), glutathione peroxidase 4(GPX4), and solute carrier family 7member 11 (SLC7A11) protein expression in the quadriceps femoris and soleus muscles, compared with CON. However, compared with LAT, DET downregulated FTH, GPX4, and SLC7A11 protein expression in the quadriceps femoris and soleus muscles. Long-term detraining during the aging phase reverses the improvement effect of lifelong exercise on oxidative stress, inflammation, ferroptosis, and muscle atrophy in aging skeletal muscle. The quadriceps femoris is more evident than the soleus, which may be related to the different changes in the Keap1/Nrf2 pathway in different skeletal muscles.

Promoting immunity with novel targeting antigen delivery vehicle based on bispecific nanobody.

As the most potent professional antigen presenting cells, dendritic cells (DCs) have been targeted in strategies to enhance vaccination efficacy. To date, targeted delivery has been mainly used for cancer therapy, with few studies focusing on vaccine antigens for animal epidemic diseases. In this study, we selected a series of mouse DC-specific nanobodies from a non-immunized camel. The four candidate nanobodies identified (Nb4, Nb13, Nb17, and Nb25), which showed efficient endocytosis of bone marrow-derived DCs, were evaluated as potential vaccine antigen targeted delivery vehicles. First, green fluorescent protein (GFP) was selected and four corresponding DCNb-GFP fusions were constructed for verification. Nb17-GFP was effective at promoting antibody production, inducing a cellular immune response, and increasing the IL-4 level. Second, foot-and-mouth disease virus (FMDV) and a FMDV-specific nanobody (Nb205) were selected and four bispecific nanobody DCNb-Nb205 fusions were generated to investigate the feasibility of a novel targeting antigen delivery vehicle. The resulting bispecific nanobody, Nb17-Nb205, could not only deliver FMDV particles instead of antigenic peptide, but also induced the production of specific antibodies, a cellular immune response, and IFN-γ and IL-4 levels upon immunization with a single subcutaneous injection. In conclusion, our results demonstrate the potential of bispecific nanobody as a novel and efficient DC-specific antigen delivery vehicle. This highlights the potential to expand targeted delivery to the field of animal epidemic diseases and provides a reference for the general application of nanotechnology in viral diseases.

Bone marrow mesenchymal stem cells paracrine TGF-ß1 to mediate the biological activity of osteoblasts in bone repair.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) are an important source of seed cells for regenerative medicine and tissue engineering therapy. BMSCs have multiple differentiation potentials and can release paracrine factors to facilitate tissue repair. Although the role of the osteogenic differentiation of BMSCs has been fully confirmed, the function and mechanism of BMSC paracrine factors in bone repair are still largely unclear. This study aimed to determine the roles of transforming growth factor beta-1 (TGF-ß1) produced by BMSCs in bone tissue repair. METHODS: To confirm our hypothesis, we used a Transwell system to coculture hBMSCs and human osteoblast-like cells without contact, which could not only avoid the interference of the osteogenic differentiation of hBMSCs but also establish the cell-cell relationship between hBMSCs and human osteoblast-like cells and provide stable paracrine substances. In the transwell coculture system, alkaline phosphatase activity, mineralized nodule formation, cell migration and chemotaxis analysis assays were conducted. RESULTS: Osteogenesis, migration and chemotaxis of osteoblast-like cells were regulated by BMSCs in a paracrine manner via the upregulation of osteogenic and migration-associated genes. A TGF-ß receptor I inhibitor (LY3200882) significantly antagonized BMSC-induced biological activity and related gene expression in osteoblast-like cells. Interestingly, coculture with osteoblast-like cells significantly increased the production of TGF-ß1 by BMSCs, and there was potential intercellular communication between BMSCs and osteoblast-like cells. CONCLUSIONS: Our findings provide evidence that the biological mechanism of BMSC-produced TGF-ß1 promotes bone regeneration and repair, providing a theoretical basis and new directions for the application of BMSC transplantation in the treatment of osteonecrosis and bone injury.

Indirect regulation of HIPPO pathway by miRNA mediates high-intensity intermittent exercise to ameliorate aging skeletal muscle function.

Exercise-induced microRNA (miRNA) and HIPPO pathways participate in the regulation of skeletal muscle plasticity but their underlying mechanisms remain unclear. We aimed to investigate the effect of high-intensity interval training (HIIT) on miRNA expression and the HIPPO pathway in the skeletal muscle of aging rats to determine its role in the amelioration of muscle aging. Thirty-six 18-month-old female rats were randomly divided into sedentary control (SED, n = 12), moderate-intensity continuous training (MICT, n = 12), and HIIT (n = 12) groups, with continuous exercise for 8 months. Quantitative reverse transcription-polymerase chain reaction, immunoblotting, KEGG enrichment, and dual-luciferase assays were performed on the target skeletal muscle. Compared with the SED group, the MICT and HIIT groups showed a significant trend of improvement in Lee's index and grip strength and a marked increase in skeletal muscle mitochondrial function, apoptosis, antioxidant, and lipolysis-related protein expression. They also exhibited PI3K/AKT pathway activation and a decrease in expression of HIPPO pathway-related proteins; 20 miRNAs were differentially expressed and enriched in the exercise group compared with the SED group, including the HIPPO pathway and metabolic pathways. Further analysis of L6 cells confirmed that miR-182 may target PTEN, which indirectly regulates HIPPO signaling, but not Mob1. the combined application of HIIT and MICT increased the antioxidant and lipolytic capacities of skeletal muscle and improved atrophy of aging skeletal muscle; HIIT was more effective than MICT. This may be related to HIIT-mediated AKT pathway activation and HIPPO pathway inhibition by miRNAs (miR-486 and miR-182).

Erratum: Excretable IR-820 for in vivo NIR-II fluorescence cerebrovascular imaging and photothermal therapy of subcutaneous tumor: Erratum.

[This corrects the article DOI: 10.7150/thno.31332.].

Conception and pregnancy outcome after laparoscopic treatment of subtle distal fallopian tube abnormalities in infertile women: a prospective cohort study.

RESEARCH QUESTION: What are conception rates and pregnancy outcomes after laparoscopic treatment of subtle distal tubal abnormalities among infertile women, and which factors relate to natural conception? DESIGN: Prospective cohort study (n = 234) conducted in a single fertility referral centre between January 2017 and December 2018. Subtle abnormalities included fimbrial agglutination, tubal diverticula, accessory ostium, fimbrial phimosis and accessory fallopian tube. Pregnancy outcomes were followed-up annually until 36 months. RESULTS: One hundred and nine patients conceived naturally (natural conception rate 46.6%), and 59 patients conceived after IVF. Term live birth rate of the natural conception group was significantly higher than the IVF conception group (86.2% versus 71.2%, chi-squared = 5.625, P = 0.018). Preterm birth (11.9% versus 0%, P = 0.001) and multiple pregnancy rates (27.1% versus 0%, P < 0.001) of the IVF conception group were significantly higher than the natural conception group. Patient age (hazard ratio = 0.917, 95% CI 0.870 to 0.967, P = 0.001), duration of infertility (hazard ratio = 0.846, 95% CI 0.740 to 0.966, P = 0.014) and concurrent types of subtle abnormalities (hazard ratio = 0.636, 95% CI 0.416 to 0.970, P = 0.036) were factors associated with natural conception. CONCLUSIONS: Laparoscopy is an effective treatment for infertile patients with subtle abnormalities, especially for young patients with a short infertile period and at most two types of subtle abnormalities. For older women, a long infertile period and more than two types of subtle abnormalities, IVF may be more suitable after laparoscopic diagnosis.

Construction of Prognostic Risk Model of Patients with Skin Cutaneous Melanoma Based on TCGA-SKCM Methylation Cohort.

Skin cutaneous melanoma (SKCM) is a common malignant skin cancer. Early diagnosis could effectively reduce SKCM patient's mortality to a large extent. We managed to construct a model to examine the prognosis of SKCM patients. The methylation-related data and clinical data of The Cancer Gene Atlas- (TCGA-) SKCM were downloaded from TCGA database. After preprocessing the methylation data, 21,861 prognosis-related methylated sites potentially associated with prognosis were obtained using the univariate Cox regression analysis and multivariate Cox regression analysis. Afterward, unsupervised clustering was used to divide the patients into 4 clusters, and weighted correlation network analysis (WGCNA) was applied to construct coexpression modules. By overlapping the CpG sites between the clusters and turquoise model, a prognostic model was established by LASSO Cox regression and multivariate Cox regression. It was found that 9 methylated sites included cg01447831, cg14845689, cg20895058, cg06506470, cg09558315, cg06373660, cg17737409, cg21577036, and cg22337438. After constructing the prognostic model, the performance of the model was validated by survival analysis and receiver operating characteristic (ROC) curve, and the independence of the model was verified by univariate and multivariate regression. It was represented that the prognostic model was reliable, and riskscore could be used as an independent prognostic factor in SKCM patients. At last, we combined clinical data and patient's riskscore to establish and testify the nomogram that could determine patient's prognosis. The results found that the reliability of the nomogram was relatively good. All in all, we constructed a prognostic model that could determine the prognosis of SKCM patients and screened 9 key methylated sites through analyzing data in TCGA-SKCM dataset. Finally, a prognostic nomogram was established combined with clinical diagnosed information and riskscore. The results are significant for improving the prognosis of SKCM patients in the future.

Case Report: Targeted Therapy with Anlotinib for a Rare Case of Spinal Cord Glioblastoma with FGFR3 Mutation.

Primary spinal cord glioblastoma (PSC GBM) is a rare disease with limited treatment options. Here, we describe a case of PSC GBM treated with anlotinib in this report. Molecular characterization confirmed the presence of the MGMT promoter unmethylated, IDH wild type, FGFR3 p.S249C and p53 p.V73fs mutations in the patient. Anlotinib is a multitarget tyrosine kinase inhibitor that target VEGFR2/3, FGFR1-4, PDGFRα/ß, and c-kit. After a partial resection of the tumor at the extramedullary invasion site, the patient was administered anlotinib 12 mg p.o. once every day (days 1-14, 21-day cycle) in combination with irinotecan chemotherapy (days 1 and 8, 21-day cycle). The patient exhibited significant symptom remission and partial response and was maintained for more than 10 months of follow-up. This case study showed that FGFR3 S249C may be a new marker for the treatment of PSC GBM with anlotinib. This case is also another strong support for molecular diagnosis and precision medicine.

V4C3TX MXene: First-principles computational and separator modification study on immobilization and catalytic conversion of polysulfide in Li-S batteries.

Many attempts have recently used rationally-designed Ti3C2Tx MXene-based materials to increase sulfur utilization and tackle the detrimental shuttle effect in Li-S batteries (LSBs) due to their merits of high electronic conductivity, considerable catalytic activity, and sulfur immobilization. Nevertheless, the investigation of applying other two-dimensional (2D) transition metal carbides in LSBs is comparatively rare. In this work, the first-principles computations predicted that V4C3Tx could boost the "adsorption-diffusion-conversion" process of lithium polysulfides (LiPSs) over that of most other metal carbides of the MXene family. Inspired by this, we prepared the V4C3Tx MXene by hydrofluoric acid (HF) etching and then used it as a functional material coating on a polypropylene (PP) separator for LSB. As expected, the V4C3Tx modified PP separator (V4C3Tx-PP) can effectively prevent the shuttle effect of LiPSs via physical blocking, chemical adsorption, and catalytic conversion, as confirmed by visual polysulfide adsorption and diffusion tests, XPS analysis, and a series of electrochemical evaluations. As a result, the LSB with a V4C3Tx-PP enabled a high capacity and enhanced cycling performance (927 mAh g-1 at 1 C and 516 mAh g-1 retained for over 800 cycles, 1 C = 1675 mA g-1). More encouragingly, the cell achieves a superior rate capability of 725 mAh g-1 at 2 C and 586 mAh g-1 at 4 C, respectively. In addition, the V4C3Tx-PP-based LSB shows a high areal capacity of 4.3 mAh cm-2, even with the sulfur loading up to 4 mg cm-2. This work expands the application types and scope of MXenes from theoretical and experimental points of view. The first use of the V4C3Tx MXene modified separator in Li-S batteries creates high potential for practical application.

Total Synthesis of Geldanamycin.

The total synthesis of geldanamycin, a well-known polyketide that exhibited potent anticancer activity by inhibiting Hsp90, was finished in 26 long linear steps with 2.65% overall yield. High convergency of the synthesis was achieved by the disconnection between C12 and C13 that gives C5-C12 and C13-C21 fragments as major building blocks. The use of an alkynyl ketone as the precursor of the C5-C12 fragment enabled a reagent-controlled establishment of C7 chirality and a highly flexible substituent exchange at C8, making the synthetic route suitable for deep-seated structural modifications on geldanamycin.

Development and validation a radiomics nomogram for diagnosing occult brain metastases in patients with stage IV lung adenocarcinoma.

BACKGROUND: To develop and validate a radiomics model using computed tomography (CT) images acquired from the first diagnosis to estimate the status of occult brain metastases (BM) in patients with stage IV lung adenocarcinoma (LADC). METHODS: One hundred and ninety-three patients who were first diagnosed with stage IV LADC were enrolled and divided into a training cohort (n=135) and a validation cohort (n=58). Then, 725 radiomic features were extracted from contoured primary tumor volumes of LADCs. Intra- and interobserver reliabilities were calculated, and the least absolute shrinkage and selection operator (LASSO) was applied for feature selection. Subsequently, a radiomics signature (Rad-Score) was built. To improve performance, a nomogram incorporating a radiomics signature and an independent clinical predictor was developed. Finally, the established signature and nomogram were assessed using receiver operating characteristic (ROC) curves and precision-recall curves (PRC). Both empirical and α-binomial model-based ROCs and PRCs were plotted, and the area under the curve (AUC) and average precision (AP) of ROCs and PRCs were calculated and compared. RESULTS: A radiomics signature and Rad-Score were constructed using eight radiomic features, and these had significant correlations with occult BM status. A nomogram was developed by incorporating a Rad-Score and the primary tumor location. The nomogram yielded an optimal AUC of 0.911 [95% confidence interval (CI): 0.903-0.919] and an AP of 0.885 (95% CI: 0.876-0.894) in the training cohort, and an AUC of 0.873 (95% CI: 0.866-0.80) and an AP of 0.827 (95% CI: 0.820-0.834) in the validation cohort using α-binomial model-based method. The calibration curve demonstrated that the nomogram showed high agreement between the actual occult BM probability and predicted by the nomogram (P=0.427). CONCLUSIONS: The nomogram incorporating a radiomics signature and a clinical risk factor achieved optimal performance after holistic assessment using unbiased indexes for diagnosing occult BM of patients who were first diagnosed with stage IV LADC.