Single-cell sequencing reveals the correlation of aggrephagy signaling and multiple myeloma immune microenvironment composition.

Aggrephagy, a type of autophagy, degrades the aggregation of misfolded protein in cells. However, the role of aggrephagy in multiple myeloma (MM) has not been fully demonstrated. In this study, we first investigated the correlation between aggrephagy signaling, MM immune microenvironment composition and disease prognosis. Single-cell RNA-seq data, including the expression profiles of 12,187 single cells from seven MM bone marrow (BM) and seven healthy BM samples, were analyzed by non-negative matrix factorization for 44 aggrephagy-related genes. Bulk RNA-seq cohorts from the Gene Expression Omnibus database were used to evaluate the prognostic value of aggrephagy-related immune cell subtypes and predict immune checkpoint blockade immunotherapeutic response in MM. Compared with healthy BM, MM BM exhibited different patterns of aggrephagy-related gene expression. In MM BM, macrophages, CD8+ T cells, B cells and natural killer cells could be grouped into four to nine aggrephagy-related subclusters. The signature of aggrephagy signaling molecule expression in the immune cells correlates with the patient's prognosis. Our investigation provides a novel view of aggrephagy signaling in MM tumor microenvironment cells, which might be a prognostic indicator and potential target for MM treatment.

Effects of saccharide type and extended heating on the Maillard reaction and physicochemical properties of high-solid gelatin gels.

This research delves into the Maillard reaction (MR) in high-solid gelatin-saccharide mixtures consisting of 8% and 72% of allulose, fructose, or fructo-oligosaccharides, which were subjected to varied duration (0-60min) of thermal processing prior to gelation. Physicochemical properties of the gels, including color, chemical composition, protein crosslinking, mechanical strength, in-vitro digestibility and antioxidant activities, were characterized. At pH ∼5.5 and intermediate water activities (0.6-0.7), fast browning was observed through sugar degradation and sugar-amine interactions, which were intensified by prolonged heating. The MR reactivity of saccharides followed: AL > FRU > FOS. Characteristic products (MRPs, e.g., α-dicarbonyls, 5-hydroxymethylfurfural, and advanced glycation end products) were identified, with the spectra of MRPs varying significantly between monosaccharides and oligosaccharides. The MR-induced protein glycation and crosslinking exhibited certain negative impacts on the gel strength and in-vitro protein digestibility. Furthermore, all gelatin-saccharide mixtures exhibited augmented antioxidant properties, with the gelatin-AL mixtures displaying the highest free radical scavenging rates.

Transoceanic ships as a source of alien dinoflagellate invasions of inland freshwater ecosystems.

Ships' ballast water and sediments have long been linked to the global transport and expansion of invasive species and thus have become a hot research topic and administrative challenge in the past decades. The relevant concerns, however, have been mainly about the ocean-to-ocean invasion and sampling practices have been almost exclusively conducted onboard. We examined and compared the dinoflagellate cysts assemblages in 49 sediment samples collected from ballast tanks of international and domestic routes ships, washing basins associated with a ship-repair yard, Jiangyin Port (PS), and the nearby area of Yangtze River (YR) during 2017-2018. A total of 43 dinoflagellates were fully identified to species level by metabarcoding, single-cyst PCR-based sequencing, cyst germination and phylogenetic analyses, including 12 species never reported from waters of China, 14 HABs-causing, 9 toxic, and 10 not strictly marine species. Our metabarcoding and single-cyst sequencing also detected many OTUs and cysts of dinoflagellates that could not be fully identified, indicating ballast tank sediments being a risky repository of currently unrecognizable invasive species. Particularly important, 10 brackish and fresh water species of dinoflagellate cysts (such as Tyrannodinium edax) were detected from the transoceanic ships, indicating these species may function as alien species potentially invading the inland rivers and adjacent lakes if these ships conduct deballast and other practices in fresh waterbodies. Significantly higher numbers of reads and OTUs of dinoflagellates in the ballast tanks and washing basins than that in PS and YR indicate a risk of releasing cysts by ships and the associated ship-repair yards to the surrounding waters. Phylogenetic analyses revealed high intra-species genetic diversity for multiple cyst species from different ballast tanks. Our work provides novel insights into the risk of bio-invasion to fresh waters conveyed in ship's ballast tank sediments and washing basins of shipyards.

Decreased RNA-binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide.

Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.

Bisphenol S enhances the cell proliferation ability of prostate cancer cells by regulating the expression of SDS.

Recent times have witnessed an increase in both incidence and mortality rates of prostate cancer. While some individuals with localized or metastatic cancer may progress slowly with a lower mortality risk, those with intermediate or high-risk cancer often face a higher likelihood of death, despite treatment. Bisphenol A (BPA) has been linked to various cancers, including prostate and breast cancer, yet the relationship between bisphenol S (BPS) and human health remains underexplored. In our study, we employed ssGSEA analysis to evaluate the BPS-associated score in a prostate cancer cohort. Additionally, differential expression analysis identified BPS-related genes within the same group. Through COX and LASSO regression analyses, we developed and validated a BPS-related risk model using ROC curve and survival analyses. A nomogram, integrating clinical characteristics with this risk model, was established for improved predictive accuracy, further substantiated by calibration curve validation. Molecular docking analysis suggested potential binding between SDS and BPS. We also conducted cell proliferation assays on C4-2 and LNCaP prostate cancer cells, revealing increased cell growth at a BPS concentration of 10-7 M, as evidenced by CCK8 and EdU assays. In summary, our findings shed light on the BPS-prostate cancer linkage, identifying BPS-associated genes, establishing a validated risk model, exploring SDS-BPS binding potential, and assessing BPS's effect on prostate cancer cell growth. These insights underscore the need for further investigation into BPS and its impact on human diseases.

Genome-wide investigation of SQUAMOSA promoter binding protein-like genes in Liriodendron and functional characterization of LcSPL2.

The plant-specific SQUAMOSA promoter-binding protein-like (SPL) transcription factors play a pivotal role in various developmental processes, including leaf morphogenesis and vegetative to reproductive phase transition. Liriodendron chinense and Liriodendron tulipifera are widely used in landscaping due to their tulip-like flowers and peculiar leaves. However, the SPL gene family in Liriodendron has not been identified and systematically characterized. We systematically identified and characterized the SPL family members in Liriodendron, including phylogeny, gene structure and syntenic analyses. Subsequently, we quantified the expression patterns of LcSPLs across various tissue sites through transcription-quantitative polymerase chain reaction (RT-qPCR) assays and identified the target gene, LcSPL2. Finally, we characterized the functions of LcSPL2 via ectopic transformation. Altogether, 17 LcSPL and 18 LtSPL genes were genome-widely identified in L. chinense and L. tulipifera, respectively. All the 35 SPLs were grouped into 9 clades. Both species had three SPL gene pairs arising from segmental duplication events, and the LcSPLs displayed high collinearity with the L. tulipifera genome. RT-qPCR assays showed that SPL genes were differentially expressed in different tissues, especially. Because LcSPL2 is highly expressed in pistils and leaves, it was selected to describe the SPL gene family of L. chinense by ectopic expression. We showed that overexpression of LcSPL2 in Arabidopsis thaliana resulted in earlier flowering and fewer rosette leaves. Moreover, we observed that overexpression of LcSPL2 in A. thaliana up-regulated the expression levels of four genes related to flower development. This study identified SPL genes in Liriodendron and characterized the function of LcSPL2 in advancing flower development.

PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

BACKGROUND: Bladder cancer is very common worldwide. PIGT is a subunit of the glycosylphosphatidylinositol transamidase which involves in tumorigenesis and invasiveness. m6A modification of mRNA has been linked to cell proliferation, tumor progression and other biological events. However, how PIGT is regulated and what is the function of PIGT in bladder cancer remains to be elucidated. METHODS: PIGT was silenced or overexpressed to study its role in regulating bladder cancer. Cell proliferation and invasion were examined with the Cell Counting Kit-8, colony formation and Transwell assay, respectively. Cellular oxygen consumption rates or extracellular acidification rates were detected by a XF24 Analyzer. Quantitative RT-PCR and immunoblots were performed to detect mRNA and protein levels. RESULTS: PIGT was overexpressed in bladder cancer. Silencing PIGT inhibited cell proliferation, oxidative phosphorylation, and glycolysis. Overexpressing PIGT promoted cell proliferation, oxidative phosphorylation, glycolysis in vitro and tumor metastasis in vivo by activating glucose transporter 1 (GLUT1). PIGT also promoted GLUT1 glycosylation and membrane trafficking. Wilms' tumor 1-associated protein (WTAP) mediated PIGT m6A modification, and m6A reader, insulin-like growth factor 2 mRNA-binding protein (IGF2BP2), binds to the methylated PIGT to promote the stability of PIGT, leading to up-regulation of PIGT. CONCLUSION: WTAP mediates PIGT m6A modification to increase the stability of PIGT via the IGF2BP2, which enhances cell proliferation, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking.

RNA-binding protein hnRNPU regulates multiple myeloma resistance to selinexor.

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells. HnRNPU knockdown-induced nuclear protein retention was examined by proteomics array. HnRNPU-conferred mRNA translation regulation was evaluated by sucrose gradient assay, RNA electrophoresis mobility shift assay, and RNA pull-down assay. We found that hnR-KD MM cells were more sensitive to selinexor-induced cell death in vitro and in mouse model. MM patients who responded to selinexor had relatively low hnRNPU expression. In brief, hnRNPU comprehensively regulated MM sensitivity to selinexor by affecting the localization of LTV1 and NMD3, and mRNA translation of MDM2 and RAN, which were involved in XPO1-mediated nuclear export of ribosome subunits and tumor suppressors. Our discoveries indicate that hnRNPU might be a possible marker to categorize MM patients for the use of Selinexor.

The role of duck LGP2 in innate immune response of host anti-tembusu virus.

Laboratory of Genetics and Physiology 2 (LGP2), along with Retinoic Acid Induced Gene-I (RIG-I) and Melanoma Differentiation Associated Gene 5, are members of the retinoic acid-inducible gene-I-like receptors (RLRs) in pattern recognition receptors, playing an important role in the host's innate immunity. Due to lacking a caspase activation and recruitment domain, LGP2 is controversially regarded as a positive or negative regulator in the antiviral response. This study aimed to explore how duck LGP2 (duLGP2) participates in duck innate immunity and its role in countering the duck Tembusu virus (DTMUV). In duck embryo fibroblast cells, the overexpression of duLGP2 significantly reduced the cell's antiviral capacity by inhibiting type I interferon (IFN) production and the expression of downstream IFN-stimulated genes. Conversely, duLGP2 knockdown had the opposite effect. For the first time, we introduced the LGP2 gene fragment into duck embryos using a lentiviral vector to ensure persistent expression and generated gene-edited ducks with LGP2 overexpression. We demonstrated that duLGP2 facilitates DTMUV replication in both in vitro and in vivo experiments, leading to robust inflammatory and antiviral responses. Interestingly, the repressive effects of duLGP2 on type I IFN production were only observed in the early stage of DTMUV infection, with type I IFN responses becoming enhanced as the viral load increased. These results indicate that duLGP2 acts as a negative regulator during the resting state and early stages of DTMUV infection. This study provides a theoretical basis for further research on duck RLRs and developing new anti-DTMUV drugs or vaccine adjuvants.

Role of Cherry Valley duck IRF1 mediated signal pathway in host anti-duck Tembusu virus.

China is the country with the largest amount of duck breeding as well as duck meat and egg production. In recent years, the emergence and spread of duck Tembusu virus (DTMUV) has become one of the important factors in reducing the amount of duck slaughter, which seriously endangers the duck breeding industry in our country. In-depth research on the mechanism of duck innate immunity facilitates the exploration of new models for the treatment of DTMUV infection. IRF1 can induce the expression of many antiviral immune factors in the animal organism and play an important role in the innate immune response. In this study, we used interfering RNA to knock down the IRF1 gene in DEF cells and then the cells were infected with DTMUV. We found that knockdown of IRF1 promoted DTMUV replication at an early stage and caused downregulation of the expression of several major pattern recognition receptors (PRRs), interleukins (IL), interferons (IFN), antiviral proteins, and MHC molecules by assay, showing that the duIRF1-mediated signaling pathway plays an extremely important role in DTMUV-induced host innate immunity. In addition, we constructed the recombinant expression plasmid pET32a(+)-duIRF1-His, and finally prepared the polyclonal antibody of duIRF1 with good specificity, hoping to provide a detection means for research on the mechanism of IRF1 in innate immunity in our laboratory and in this field.

The stratification and prognostic importance of molecular and immune landscapes in clear cell renal cell carcinoma.

The aim of our research is to explore the various characteristics and genetic profiles of clear cell renal cell carcinoma (ccRCC) in order to discover possible predictors of prognosis and targets for treatment. By utilizing ssGSEA scores, we categorized patients with ccRCC into groups based on their phenotype, distinguishing between low and high. This categorization revealed significant variations in the expression of crucial immune checkpoint genes and Human Leukocyte Antigen (HLA) genes, suggesting the presence of a potential immune evasion tactic in different subtypes of ccRCC. A predictive model was built using genes that are expressed differently and linked to cell death, showing strong effectiveness in categorizing patient risk. Furthermore, we discovered a noteworthy correlation among risk scores, infiltration of immune cells, the expression of genes related to immune checkpoint inhibitors, and diverse clinical features. This indicates that our scoring system for risk could function as a comprehensive gauge of the severity of the disease. The examination of the mutational terrain further highlighted the predominance of particular genetic changes, including VHL and PBRM1 missense mutations. Finally, we have discovered the function of DKK1 in facilitating cell death in ccRCC, presenting an additional possibility for therapeutic intervention. The results of our study suggest the possibility of incorporating molecular information into clinical prediction, which could lead to personalized treatment approaches in ccRCC.

Methylcrotonyl-CoA carboxylase subunit 1 (MCCA) regulates multidrug resistance in multiple myeloma.

AIMS: This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM). MATERIALS AND METHODS: The apoptosis kit and CCK-8 reagent were used to detect drug-induced cell apoptosis and viability. Immunoprecipitation, immunofluorescence staining, and protein structural simulation were used to detect the interaction between MCCA and Bad. Immunodeficient mice were injected with ARD cells and treated with bortezomib. Changes in tumor burden were recorded by bioluminescence imaging, and κ light chain content in the blood of mice was detected by enzyme-linked immunoassay. KEY FINDINGS: Patients with high MCCA expression from a primary MM dataset had superior overall survival. After treatment with different anti-MM drugs, MCCA knockdown MM (MCCA-KD) cells had higher survival rates than control knockdown (CTR-KD) cells (p < 0.05). Mechanistic studies have revealed that MCCA-KD cells had dysfunctional mitochondria with decreased Bax and Bad levels and increased Bcl-xl and Mcl-1 levels. Furthermore, that MCCA and Bad demonstrated protein-protein interactions. The half-life of Bad in MCCA-KD cells is significantly shorter than that in CTR-KD cells (7.34 vs. 2.42 h, p < 0.05). In a human MM xenograft mouse model, we confirmed that MCCA-KD tumors had a poor response to anti-MM drugs in vivo. Finally, we showed that MCCA might contribute to multidrug resistance in different human cancers, particularly in solid tumors. SIGNIFICANCE: Our findings demonstrated a novel function of MCCA in multidrug resistance. The lack of MCCA expression promoted antiapoptotic cell signaling in MM cells.

Super-enhancer-associated SNHG15 cooperating with FOSL1 contributes to bladder cancer progression through the WNT pathway.

Small nucleolar RNA host gene 15 (SNHG15) plays an oncogenic role in many cancers. However, the role of SNHG15 in bladder cancer (BLCA) remains unclear. In this study, the regulation of SNHG15 on the activities of BLCA cells (T24 and RT112) was investigated. In detail, super-enhancers (SEs), differentially expressed genes, and functional enrichment were detected by bioinformatic analyses. Mutant cell lines lacking SNHG15-SEs were established using CRISPR-Cas9. Relative gene expression was detected by quantitative polymerase chain reaction (qPCR), western blot, in situ hybridization, and immunohistochemistry assays. Cell senescence, apoptosis, viability, and proliferation were measured. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assays were conducted to analyze the interactions between genes. A novel super-enhancer of SNHG15 (SNHG15-SEs) was discovered in several BLCA datasets. The deletion of SNHG15-SEs resulted in a significant downregulation of SNHG15. Mechanistically, the core active region of SNHG15-SEs recruited the transcription factor FOSL1 to facilitate the SNHG15 transcription, thereby inducing the proliferation and metastasis of BLCA cells. Deletion of SNHG15-SEs inhibited the growth and metastasis of T24 and RT112 cells by inactivating the WNT/CTNNB1 pathway activation. Overexpression of FOSL1 in SNHG15-SEs restored the cell proliferation and metastasis. Next, a xenograft mouse model showed that SNHG15-SEs deletion inhibited the proliferation and metastasis of BLCA cells in vivo. Collectively, our data indicate that SNHG15-SEs recruit FOSL1 to promote the expression of SNHG15 which interacts with CTNNB1 in the nucleus to activate the transcription of ADAM12, leading to the malignance of BLCA cells.

Research Note: Genetic characterization of novel duck reoviruses from Shandong Province, China in 2022.

Since 2005, novel duck reoviruses have been outbreaks in duck breeding areas such as central China and South China. In recent years, the incidence rate of this disease is still increasing, bringing serious economic losses to waterfowl breeding industry. This study isolated 3 novel duck reoviruses (NDRV-SDLS, NDRV-SDWF, and NDRV-SDYC) from sick ducks in 3 local duck farms in Shandong Province. The study aimed to investigate the characteristics of these viruses. The virus is inoculated into duck embryo fibroblasts, where the virus replicates to produce syncytium and dies within 3 to 5 d. The viruses were also isolated from infected ducks, and RT-PCR amplified the whole genomes after passage purification in duck embryos. The resulting whole genome was analyzed for genetic evolution. The total length of the gene sequencing was 23,418 bp, divided into 10 fragments. Gene sequence comparison showed that the 3 strains had high similarity with novel duck reoviruses (NDRV) but low similarity with chicken-origin reovirus (chicken ARV) and Muscovy duck reovirus (MDRV), especially in the σC segment. Phylogenetic analysis of the 10 fragments showed that the 3 isolates constituted the same evolutionary clade as other DRV reference strains and were far related to ARV and MDRV in different evolutionary clades. The results of all 10 segments indicate that the isolates are in the evolutionary branch of NDRV, suggesting that the novel waterfowl reovirus is the dominant circulating strain in Shandong. This study complements the gene bank information of NDRV and provides references for vaccine research and disease prediction of NDRV in Shandong.

Research Note: Complete genome cloning and genetic evolution analysis of four Cherry Valley duck circovirus strains in China in 2022.

In recent years, with the expansion of duck breeding industry in China, the infection rate of duck circovirus (DuCV) in duck and the mixed infection rate of DuCV with other diseases increased significantly, which seriously endanger the development of duck breeding industry. To study the epidemic status of duck circovirus in China, analyze the virus's genetics and evolution, and establish a foundation for scientific prevention and control of duck circovirus, our laboratory collected 4 disease materials preliminarily diagnosed as duck circovirus infections. Conventional PCR was used to amplify 4 strains of duck circovirus with a full length of 1993bp, and their sequences were compared and analyzed. The analysis showed that the 4 DuCVs had typical circovirus characteristics, including 3 major ORFs: ORFV1 (Rep protein), ORFC1 (Cap protein), ORFC2 (apoptosis-related protein), and a stem ring structure. The 4 strains were compared with 22 other reference strains, and the results revealed that all 4 strains belonged to the DuCV-I type represented by the German strain AY228555. Furthermore, the homology between the 4 DuCVs and the reference strains was up to 98.6%, which help us to understand the genotype and genetic variation of DuCV in these regions and provide a reference for the prevention and control of DuCV.

Combinations of ivermectin with proteasome inhibitors induce synergistic lethality in multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed that ivermectin exerted anti-MM effects and significantly synergized with proteasome inhibitors in vitro and in vivo. Ivermectin alone exhibited mild anti-MM activity in vitro. Further investigation suggested that ivermectin inhibited proteasome activity in the nucleus by repressing the nuclear import of proteasome subunits, such as PSMB5-7 and PSMA3-4. Therefore, ivermectin treatment caused the accumulation of ubiquitylated proteins and the activation of the UPR pathway in MM cells. Furthermore, ivermectin treatment caused DNA damage and DNA damage response (DDR) signaling pathway activation in MM cells. Ivermectin and bortezomib exhibited synergized anti-MM activity in vitro. The dual-drug treatment resulted in synergistic inhibition of proteasome activity and increased DNA damage. An in vivo study using a human MM cell line xenograft mouse model showed that ivermectin and bortezomib efficiently repressed MM tumor growth in vivo, while the dual-drug treatment was well tolerated by experimental animals. Overall, our results demonstrated that ivermectin alone or cotreated with bortezomib might be promising in MM treatment.

Identification of the novel therapeutic targets and biomarkers associated of prostate cancer with cancer-associated fibroblasts (CAFs).

Globally, prostate cancer remains a leading cause of mortality and morbidity despite advances in treatment. Research on prostate cancer has primarily focused on the malignant epithelium, but the tumor microenvironment has recently been recognized as an important factor in the progression of prostate cancer. Cancer-associated fibroblasts (CAFs) play an important role in prostate cancer progression among multiple cell types in the tumor microenvironment. In order to develop new treatments and identify predictive and prognostic biomarkers for CAFs, further research is needed to understand the mechanism of action of prostate cancer and CAF. In this work, we performed the single-cell RNA sequence analysis to obtain the biomarkers for CAFs, and ten genes were finally regarded as the marker genes for CAFs. Based on the ssGSEA algorithm, the prostate cancer cohort was divided into low- and high-CAFs groups. Further analysis revealed that the CAFs-score is associated with many immune-related cells and immune-related pathways. In addition, between the low- and high-CAFs tissues, a total of 127 hub genes were discovered, which is specific in CAFs. After constructing the prognostic prediction model, SLPI, VSIG2, CENPF, SLC7A1, SMC4, and ITPR2 were finally regarded as the key genes in the prognosis of patients with prostate cancer. Each patient was assigned with the risk score as follows: SLPI* 0.000584811158157081 + VSIG2 * -0.01190627068889 + CENPF * -0.317826812875334 + SLC7A1 * -0.0410213995358753 + SMC4 * 0.202544454923637 + ITPR2 * -0.0824652047622673 + TOP2A * 0.140312081524807 + OR51E2 * -0.00136602095885459. The GSVA revealed the biological features of CAFs, many cancer-related pathways, such as the adipocytokine signaling pathway, ERBB signaling pathway, GnRH signaling pathway, insulin signaling pathway, mTOR signaling pathway and PPAR signaling pathway are closely associated with CAFs. As a result of these observations, similar transcriptomics may be involved in the transition from normal fibroblasts to CAFs in adjacent tissues. As one of the biomarkers for CAFs, CENPF can promote the proliferation ability of prostate cancer cells. The overexpress of CENPF could promote the proliferation ability of prostate cancer cells. In conclusion, we discuss the potential prognostic and therapeutic value of CAF-dependent pathways in prostate cancer.

Molecular Targets of Shenqi Dihuang, A Traditional Chinese Herbal Medicine, and Its Potential Role in Renal Cell Carcinoma Therapy.

Chinese herbal medicine (CHM), which includes herbal slices and proprietary products, is widely used in China. Shenqi Dihuang (SQDH) is a traditional Chinese medicine (TCM) formula with ingredients that affect tumor growth. Despite recent advances in prognosis, patients with renal cell carcinoma (RCC) cannot currently receive curative treatment. The present study aimed to explore the potential target genes closely associated with SQDH. The gene expression data for SQDH and RCC were obtained from the TCMSP and TCGA databases. The SQDH-based prognostic prediction model reveals a strong correlation between RCC and SQDH. In addition, the immune cell infiltration analysis indicated that SQDH might be associated with the immune response of RCC patients. Based on this, we successfully built the prognostic prediction model using SQDH-related genes. The results demonstrated that CCND1 and NR3C2 are closely associated with the prognosis of RCC patients. Finally, the pathways enrichment analysis revealed that response to oxidative stress, cyclin binding, programmed cell death, and immune response are the most enriched pathways in CCND1. Furthermore, transcription regulator activity, regulation of cell population proliferation, and cyclin binding are closely associated with the NR3C2.

Liposome-Encapsulated Melphalan Exhibits Potent Antimyeloma Activity and Reduced Toxicity.

Multiple myeloma (MM), a plasma cell cancer in bone marrow, remains an incurable disease. Melphalan, an alkylating agent, is a conventional anticancer drug that is still widely used for MM treatment in clinics. However, melphalan-induced organ toxicity and side effects are common. In this study, we loaded melphalan into a liposomal capsule and constituted liposomal melphalan (liposomal MEL). Liposomal MEL particles were approximately 120 nm in size and stable in vitro. The liposomal particles could be effectively taken up by MM cells. In vitro cytotoxicity assays using MM cell lines and primary MM cells showed that liposomal MEL exhibited similar anti-MM activity compared to an equivalent amount of free melphalan (free MEL) compound. In animal models, liposomal particles had bone marrow enrichment and prolonged half-life in vivo. Liposomal MEL exposure resulted in less liver and colon organ toxicity than exposure to an equivalent amount of free MEL-treated mice. Importantly, liposomal MEL had potent anti-MM activity in vivo in a human MM xenograft mouse model. Overall, our findings suggested that liposome-encapsulated melphalan was an effective drug modification of the melphalan compound and showed promise in MM treatment.

Overexpression of LtuHB6 from Liriodendron tulipifera causes lobed-leaf formation in Arabidopsis thaliana.

Liriodendron tulipifera L. is an ornamental tree species with extraordinarily lobed leaves. However, the mechanisms underlying lobed leaf formation in plants remain unclear. The transcription factor, ARABIDOPSIS THALIANA HOMEBOX 6 (HB6), plays a role in regulating leaf margin development. HB6 is involved in cell division and differentiation of developmental organs and negatively regulates abscisic acid (ABA) signal transmission under external abiotic stress; it is unclear whether HB6 performs a pivotal role in leaf morphogenesis in L. tulipifera. In this study, full-length LtuHB6 from L. tulipifera was heterologously expressed in tobacco and Arabidopsis thaliana; its expression pattern was analyzed to determine its potential role in leaf development. In addition, LtuHB6 is localized in the nucleus and cell membrane of tobacco leaves. The expression of LtuHB6 was highest in mature leaves compared to the other stages of leaf development (bud growth, young leaves, and leaf senescence). Transgenic A. thaliana plants overexpressing LtuHB6 exhibited an abnormal phenotype with lobed leaves. Moreover, LtuHB6 overexpression significantly affected the expression of seven genes related to leaf serration in the initial stage of leaf primordia and altered the expression levels of hormonal genes. Our findings indicate that LtuHB6 is an essential regulatory factor in L. tulipifera lobed-leaf formation and is involved in regulating and responding to hormones. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01254-9.