Engineered Microorganisms for Advancing Tumor Therapy.

Engineered microorganisms have attracted significant interest as a unique therapeutic platform in tumor treatment. Compared with conventional cancer treatment strategies, engineering microorganism-based systems provide various distinct advantages, such as the intrinsic capability in targeting tumors, their inherent immunogenicity, in situ production of antitumor agents, and multiple synergistic functions to fight against tumors. Herein, the design, preparation, and application of the engineered microorganisms for advanced tumor therapy are thoroughly reviewed. This review presents a comprehensive survey of innovative tumor therapeutic strategies based on a series of representative engineered microorganisms, including bacteria, viruses, microalgae, and fungi. Specifically, it offers extensive analyses of the design principles, engineering strategies, and tumor therapeutic mechanisms, as well as the advantages and limitations of different engineered microorganism-based systems. Finally, the current challenges and future research prospects in this field, which can inspire new ideas for the design of creative tumor therapy paradigms utilizing engineered microorganisms and facilitate their clinical applications, are discussed.

Acteoside protects podocyte against apoptosis through regulating AKT/GSK-3ß signaling pathway in db/db mice.

BACKGROUND: Podocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act's renoprotective actions in db/db mice. METHODS: We adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining. RESULTS: The albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3ß (AKT/GSK-3ß) signaling pathway was repressed. CONCLUSIONS: By inhibiting the AKT/GSK-3ß signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.

Sesamol serves as a p53 stabilizer to relieve rheumatoid arthritis progression and inhibits the growth of synovial organoids.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame (Sesamum indicum L.) with various biological activities. PURPOSE: The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment. METHODS: CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression. RESULTS: Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA. CONCLUSIONS: Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.

Arecoline hydrobromide suppresses PI3K/AKT pathway in rheumatoid arthritis synovial fibroblasts and relieves collagen-induced arthritis in mice.

OBJECTIVE: This study investigated the effectiveness of arecoline hydrobromide (AH) on the functions of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and collagen-induced arthritis (CIA) mice. METHODS: Immunofluorescence was used to identify RA-FLSs. Cell Counting Kit-8 (CCK-8) was used to determine the viability of RA-FLSs and the half maximal inhibitory concentration (IC50) of AH. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to detect DNA replication in RA-FLSs. Cell cycle and apoptosis were examined by flow cytometry. Migration and invasion, as well as wound healing assays, were employed to determine cell migration and invasion ability. Proteins and mRNA expression levels were investigated using Western blot, quantitative real-time PCR (RT-qPCR), and immunofluorescence. The CIA mice model was used to assess the effect of AH in vivo. RNA-sequencing (RNA-seq) was used to find the potential signaling pathways of AH against RA, and Western blot was used to verify the key signaling pathway of AH on RA-FLSs. Network pharmacology and molecular docking were used to predict drug targets. RESULTS: AH inhibited the proliferation and DNA replication of RA-FLSs, promoted cell cycle arrest by reducing the levels of cyclin-dependent kinase 1 (CDK1), cyclin A2, and cyclin B1, promoted apoptosis by suppressing B-cell lymphoma-2 (Bcl-2) expression, and suppressed migration and invasion by inhibiting vimentin expression in RA-FLSs. AH was also effective in relieving arthritis in vivo. RNA sequencing analyses suggested that AH inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in RA-FLSs, which was also confirmed in Western blot analysis. Furthermore, network pharmacology and molecular docking suggested that F2, MAPK14, SRC, AKT1, and CTSK might be the direct targets of AH. CONCLUSION: AH can modulate the pathological process of RA-FLSs by blocking the PI3K/AKT pathway and relieve CIA in mice, making it a potential new small molecule candidate.

Multi-Bioinspired Functional Conductive Hydrogel Patches for Wound Healing Management.

Many hydrogel patches are developed to solve the pervasive and severe challenge of complex wound healing, while most of them still lack satisfactory controllability and comprehensive functionality. Herein, inspired by multiple creatures, including octopuses and snails, a novel muti-functional hydrogel patch is presented with controlled adhesion, antibacterial, drug release features, and multiple monitoring functions for intelligent wound healing management. The patch with micro suction-cup actuator array and a tensile backing layer is composed of tannin grafted gelatin, Ag-tannin nanoparticles, polyacrylamide (PAAm) and poly(N-isopropylacrylamide) (PNIPAm). In virtue of the photothermal gel-sol transition of tannin grafted gelatin and Ag-tannin nanoparticles, the patches exert a dual anti-microbial effect and temperature-sensitive snail mucus-like features. In addition, as the "suction-cups" consisting of thermal responsive PNIPAm can undergo a contract-relax transformation, the medical patches can adhere to the objects reversibly and responsively, and release their loaded vascular endothelial growth factor (VEGF) controllably for wound healing. More attractively, benefiting from their fatigue resistance, self-healing ability of the tensile double network hydrogel, and electrical conductivity of Ag-tannin nanoparticles, the proposed patches can report multiple wound physiology parameters sensitively and continuously. Thus, it is believed that this multi-bioinspired patch has immense potential for future wound healing management.

Construction of engineered 3D islet micro-tissue using porcine decellularized ECM for the treatment of diabetes.

Islet transplantation improves diabetes patients' long-term blood glucose control, but its success and utility are limited by cadaver availability, quality, and considerable islet loss after transplantation due to ischemia and inadequate angiogenesis. This study used adipose, pancreatic, and liver tissue decellularized extracellular matrix (dECM) hydrogels in an effort to recapitulate the islet sites inside the pancreas in vitro, and successfully generated viable and functional heterocellular islet micro-tissues using islet cells, human umbilical vein endothelial cells, and adipose-derived mesenchymal stem cells. The three-dimensional (3D) islet micro-tissues maintained prolonged viability and normal secretory function, and showed high drug sensitivity in drug testing. Meanwhile, the 3D islet micro-tissues significantly enhanced survival and graft function in a mouse model of diabetes. These supportive 3D physiomimetic dECM hydrogels can be used not only for islet micro-tissue culture in vitro, but also have great promise for islet transplantation for the treatment of diabetes.

Pt(IV) prodrug initiated microparticles from microfluidics for tumor chemo-, photothermal and photodynamic combination therapy.

Multimodal treatment modalities hold great potential for cancer therapy, thus current efforts are focusing on the development of more effective and practical synergistic therapeutic platforms. Herein, we present a novel trans, trans,trans-[Pt(N3)2(OH)2(py)2] (Pt(IV)) prodrug-initiated hydrogel microparticles (MICG-Pt) with indocyanine green (ICG) encapsulation by microfluidics for efficiently synergistic chemo-, photothermal (PTT) and photodynamic therapy (PDT). The employed Pt(IV) could not only serves as an initiator to generate azidyl radical (N3 •) for photo-polymerization of methacrylate gelatin (GelMA) matrix, but also be reduced to high cytotoxic platinum(II) (Pt(II)) species for tumor chemotherapy. The laden ICG with highly photothermal heating ability and intrinsic reactive oxygen species (ROS) productivity endows the MICG-Pt with effective PTT/PDT performances upon near-infrared (NIR) light irradiation. In addition, benefiting from the production of oxygen during the photo-activation process of Pt(IV), the PDT efficacy of ICG-laden MICG-Pt could be further enhanced. Based on these advantages, we have demonstrated that the MICG-Pt could significantly eliminate cancer cells in vitro, and remarkably suppressed the tumor growth in vivo via synergistic chemotherapy, PTT, and PDT. These results indicate that such Pt(IV)-initiated hydrogel microparticles are ideal candidates of multimodal treatment platforms, holding great prospects for cancer therapy.

Ovarian sensitivity index can be used as a more sensitive indicator than follicular output rate to predict IVF/ICSI outcomes in patients of normal expected ovarian response stimulated with GnRH antagonist protocol.

This retrospective study was performed to investigate the predictive power of the Ovarian Sensitivity Index (OSI) for IVF/ICSI outcomes in infertile patients who were of normal expected ovarian response. A total of 912 infertile patients who underwent GnRH antagonist protocol between January 2017 to August 2019 at the Medical Center for Human Reproduction, Beijing Chao-Yang Hospital were included. All patients completed the full oocyte retrieval cycle and either had a live birth or had no embryos left. OSI was significantly lower in patients with a live birth (196.0 ± 120.4 in the live birth group vs 276.4 ± 235.7 in the non-live birth group, p < 0.001) while follicular output rate (FORT, defined as the ratio of pre-ovulatory follicle count on hCG day x 100/small antral follicle count at baseline) showed no significant difference. Patients were divided into low, average and high OSI groups and analysed in tertiles. From the low to the high OSI group, the cumulative live birth rate (CLBR) decreased dramatically (72.7 vs 67.2 vs 54.8%, p < 0.001). Multivariate regression analysis showed that OSI was an independent factor affecting CLBR (OR: 0.996, 95%CI: 0.995-0.998, p < 0.001) in our study population. In conclusion, OSI can be used as an independent indicator to distinguish fecundity in infertile patients with normal expected ovarian response and is probably more sensitive than FORT.

Protective effect of ginsenoside Rd on military aviation noise-induced cochlear hair cell damage in guinea pigs.

Noise pollution has become one of the important social hazards that endanger the auditory system of residents, causing noise-induced hearing loss (NIHL). Oxidative stress has a significant role in the pathogenesis of NIHL, in which the silent information regulator 1(SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway is closely engaged. Ginsenoside Rd (GSRd), a main monomer extract from ginseng plants, has been confirmed to suppress oxidative stress. Therefore, the hypothesis that GSRd may attenuate noise-induced cochlear hair cell loss seemed promising. Forty-eight male guinea pigs were randomly divided into four groups: control, noise exposure, GSRd treatment (30 mg/kg Rd for 10d + noise), and experimental control (30 mg/kg glycerol + noise). The experimental groups received military helicopter noise exposure at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling (TUNEL) and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters, were used as readouts. Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly mitigated hearing threshold shifts, ameliorated outer hair cell loss and lodging or loss of cilia, and improved apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd alleviated the noise-induced cochlear redox injury by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreasing malondialdehyde (MDA) levels, and enhancing the activity of SIRT1 and PGC-1α messenger ribonucleic acid (mRNA) and protein expression. In conclusion, GSRd can improve structural and oxidative damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.

Photopolymerized 3D Printing Scaffolds with Pt(IV) Prodrug Initiator for Postsurgical Tumor Treatment.

Biomedical scaffolds have shown great success in postsurgical tumor treatment; their current efforts are focusing on eradicating residual tumor cells and circulating tumor cells and simultaneously repairing postoperative tissue defects. Herein, we report a novel photopolymerized 3D scaffold with Pt(IV) prodrug initiator to achieve the desired features for tumor comprehensive therapy. The Pt-GelMA scaffold was fabricated from the microfluidic 3D printing of methacrylate gelatin (GelMA) bioinks through a Pt(IV)-induced photocrosslinked process without any other additional photoinitiator and chemotherapeutic drug. Thus, the resultant scaffold displayed efficient cell killing ability against breast cancer cells in vitro and significantly inhibited the local tumor growth and distant metastases on an orthotopic postoperative breast cancer model in vivo. Besides, benefiting from their ordered porous structures and favorable biocompatibility, the scaffolds supported the cell attachment, spreading, and proliferation of normal cells in vitro; could facilitate the nutrient transportation; and induced new tissue ingrowth for repairing tissue defects caused by surgery. These properties indicate that such 3D printing scaffold is a promising candidate for efficient postoperative tumor treatment in the practical application.

Cationic starch modified bentonite-alginate nanocomposites for highly controlled diffusion release of pesticides.

To promote the controlled release efficacy of nanocomposites based on alginate and bentonite, (3-chloro-2-hydroxypropyl)trimethyl ammonium grafted starch was prepared and used as modifying agent of the clay. The nanocomposites were characterized by FTIR, XRD, SEM and TG analysis, to reveal the structural effects on the swelling property of the matrix and the release of alachlor, the model compound. Thermodynamics study indicated that the adsorption of alachlor on the bentonite was dominated by hydrophobic interaction with the siloxane surface of the clay and enhanced by the binding of the cationic starch. The electrostatic attraction between alginate and cationic starch bound on the surface also decreased the aggregation of bentonite platelets, leading to a more compact structure of the nanocomposites. The higher adsorption capability and lower permeability of the matrix resulted in a slower release of alachlor, which was dominated by Fickian diffusion mechanism. The release of alachlor first decreased and then increased with increasing content of bentonite and cationic starch modified bentonite in the nanocomposites, reaching a minimum around weight percentage 10%, at which the time taken for 50% of active ingredient to be released were 4.4 and 7.3 times that for the release from pure alginate hydrogel.

Dynamically Responsive Scaffolds from Microfluidic 3D Printing for Skin Flap Regeneration.

Biological scaffolds hold promising perspectives for random skin flap regeneration, while the practical application is greatly limited by their insufficient vascularization ability and the lack of responsiveness during the dynamical healing process. Herein, a novel MXene-incorporated hollow fibrous (MX-HF) scaffold with dynamically responsive channels is presented for promoting vascularization and skin flap regeneration by using a microfluidic-assisted 3D printing strategy. Benefiting from the photothermal conversion capacity of the MXene nanosheets and temperature-responsive ability of poly(NIPAM) hydrogels in the MX-HF scaffolds, they display a near-infrared (NIR)-responsive shrinkage/swelling behavior, which facilitates the cell penetration into the scaffold channels from the surrounding environment. Moreover, by incorporating vascular endothelial growth factor (VEGF) into the hydrogel matrix for controllable delivery, the MX-HF scaffolds can achieve promoted proliferation, migration, and proangiogenic effects of endothelial cells under NIR irradiation. It is further demonstrated in vivo that the NIR-responsive VEGF@MX-HF scaffolds can effectively improve skin flap survival by promoting angiogenesis, decreasing inflammation, and attenuating apoptosis in skin flaps. Thus, it is believed that such responsive MX-HF scaffolds are promising candidates for clinical random skin flap regeneration as well as other diverse tissue engineering applications.

Upregulated SPAG6 promotes acute myeloid leukemia progression through MYO1D that regulates the EGFR family expression.

Chromosomal aberrations and gene mutations have been considered to be the major reasons for high recurrence rates and poor survival among acute myeloid leukemia (AML) patients. However, the underlying molecular mechanism of AML gene mutation remains largely unclear. Here, we show that SPAG6 (sperm-associated antigen 6), one of the most markedly increased SPAG genes in AML, significantly contributed to the proliferation and migration of leukemic cells. SPAG6 was highly expressed in AML, and its upregulation was negatively correlated with the prognosis of the disease. In vitro, SPAG6 promoted the proliferation and migration of leukemia cells and promoted cell cycle progression from the G1 phase to the S phase. In vivo, low expression of SPAG6 reduced the proliferation and infiltration of leukemia cells and prolonged the survival of xenograft tumor mice. Furthermore, immunoprecipitation and mass spectrometry analysis showed that SPAG6 interacts with MYO1D (myosin 1D). Specifically, overexpression of SPAG6 promoted the translocation of MYO1D into the cell membrane, thus upgrading the expression level of the EGFR family and thereby promoting the progression of AML. Overall, our study found that SPAG6 combined with MYO1D and translocated MYO1D from the cytosol to the cytomembrane, which induced the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B) signaling and ERK (extracellular signal-regulated kinase) signaling pathway to regulate the growth and prognosis of AML. SPAG6 may become a new target gene for the treatment of AML.

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway.

BACKGROUND: Radiation-induced lung injury (RILI) is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remains unknown. METHODS: We successfully obtained Sox9CreER, RosatdTomato and RosaDTA mice and identified Sox9-expressing cells through lineage tracing. Then, we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9-expressing cells during lung regeneration via an online single-cell RNA-seq dataset. RESULTS: In our study, we demonstrated that Sox9-expressing cells promote the regeneration of lung tissues and that ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of an online scRNA-Seq dataset revealed that the PI3K/AKT pathway is enriched in Sox9-expressing cells during lung epithelium regeneration. Finally, the AKT inhibitor perifosine suppressed the regenerative effects of Sox9-expressing cells and the AKT pathway agonist promotes proliferation and differentiation. CONCLUSIONS: Taken together, the findings of our study suggest that Sox9-expressing cells may serve as a therapeutic target in lung tissue after RILI.

Discovery of sensorineural hearing loss and ossicle deformity in a Chinese Li nationality family with spondyloepiphyseal dysplasia congenita caused by p.G504S mutation of COL2A1.

BACKGROUND: Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, and flattened vertebral bodies. COL2A1 has been confirmed as the pathogenic gene. Hearing loss represents an infrequent manifestation for 25-30% of patients with SEDC. The characteristics of the hearing impairment were rarely documented. METHODS: Audiological, ophthalmic, imaging examinations were conducted on the family members. The whole exome sequencing (WES) was performed to detect the candidate gene, and the Sanger sequencing was used to confirm the causative variation. RESULTS: COL2A1 c.1510G>A (p.G504S), a hot spot variation, was identified as the disease-causing mutation of the Chinese Li nationality family with SEDC. This variation was co-segregated with the SEDC phenotype in the family and was absent in the 1000 Genomes Project, ESP and ExAC. Clinically, several manifestations were first demonstrated in SEDC patients caused by p.G504S, including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Other classical SEDC manifestations such as bones and joints pain, midfacial dysplasia, disproportionate short stature, spinal deformity, thoracocyllosis, coxa arthropathy, myopia and waddling gait were also showed in the family patients. CONCLUSION: We first identified the mutation p.G504S in COL2A1 gene as the pathogenesis in a Chinese Li nationality family and reported the correlation between p.G504S and atypical clinical phenotypes including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Our findings would extend the phenotypic spectrum of SEDC and deepen clinicians' understanding of genotype-phenotype correlation of the disease.

Biochemical and metabolic responses of the deep-sea mussel Bathymodiolus platifrons to cadmium and copper exposure.

Greater interest in commercial deep-sea mining has been accompanied by mounting environmental concerns, including metal contamination resulting from mining activities. However, little is known about the toxic effects of metal exposure on deep-sea life. Given its ability to accumulate metals from the surrounding environment, its wide distribution at both vents and seeps, and its high abundance, the deep-sea mussel Bathymodiolus platifrons could serve as an ideal model to investigate the toxicological responses of deep-sea organisms to metal exposure. Here, we evaluated metal accumulation, traditional metal-related biomarkers, namely acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase, catalase, reduced glutathione, metallothioneins, and malondialdehyde, as well as metabolic profiles in the gills of B. platifrons after a 7-day exposure to copper (100 µg/L), cadmium (500 µg/L), or copper-plus-cadmium treatments (100 µg/L Cu and 500 µg/L Cd). Metal exposure concentrations selected in this study can be found in deep-sea hydrothermal environments. Metal exposure resulted in significant metal accumulation in the gills of the mussel, indicating that B. platifrons has promise for use as an indicator of deep-sea metal pollution levels. Traditional biomarkers (AKP, ACP, and measured antioxidants) revealed cellular injury and oxidative stress in mussels following metal exposure. Metabolic responses in the three treatment groups indicated that metal exposure perturbed osmoregulation, energy metabolism, and nucleotide metabolism in mussels, in a response marked by differentially altered levels of amino acids, hypotaurine, betaine, succinate, glucose 6-phosphate, fructose 6-phosphate, guanosine, guanosine 5'-monophosphate, and inosine. Nevertheless, several uniquely altered metabolites were found in each treatment exposure group, suggesting dissimilar modes of toxicity between the two metal types. In the Cd-exposed group, the monosaccharide D-allose, which is involved in suppressing mitochondrial ROS production, was downregulated, a response consistent with oxidative stress in Cd-exposed B. platifrons. In the Cu-exposed group, the detected alterations in dopamine, dopamine-related, and serotonin-related metabolites together suggest disturbed neurotransmission in Cu-exposed B. platifrons. In the Cu-plus-Cd group, we detected a decline in fatty acid levels, implying that exposure to both metals jointly exerted a negative influence on the physiological functioning of the mussel. To the best of our knowledge, this is the first study to investigate changes in metabolite profiles in Bathymodiolus mussels exposed to metal. The findings reported here advance our understanding of the adverse impact of metal exposure on deep-sea life and can inform deep-sea mining assessments through the use of multiple biomarkers.

Identification of a lncRNA prognostic signature-related to stem cell index and its significance in colorectal cancer.

Background: The relationship between long noncoding RNAs (lncRNAs) and the mRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAs and their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

Lay abstract Previous evidence has indicated that the mRNA stem index (mRNAsi) is representative of the stemness of cancer stem cells (CSCs), whereas long noncoding RNAs (lncRNAs) may be crucial regulators in CSC phenotype. Nevertheless, the relationship between lncRNAs and mRNAsi in CRC is still unclear. Our results show that the mRNAsi was negatively related to pathological features and positively related to prognosis in CRC. Five mRNAsi-related lncRNAs were further identified and developed as a prognostic signature that could independently predict survival in CRC patients due to the five mRNAsi-related lncRNAs being involved in several pathways of CSCs and malignant cancer cell phenotypes, indicating the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

3D printed in vitro tumor tissue model of colorectal cancer.

Rationale: The tumor microenvironment (TME) determines tumor progression and affects clinical therapy. Its basic components include cancer-associated fibroblasts (CAFs) and tumor-associated endothelial cells (TECs), both of which constitute the tumor matrix and microvascular network. The ability to simulate interactions between cells and extracellular matrix in a TME in vitro can assist the elucidation of cancer growth and evaluate the efficiency of therapies. Methods: In the present study, an in vitro 3D model of tumor tissue that mimicked in vivo cell physiological function was developed using tumor-associated stromal cells. Colorectal cancer cells, CAFs, and TECs were co-cultured on 3D-printed scaffolds so as to constitute an extracellular matrix (ECM) that allowed cell processes such as adhesion, stemness, proliferation, and vascularization to take place. Normal stromal cells were activated and reprogrammed into tumor-related stromal cells to construct a TME of tumor tissues. Results: The activated stromal cells overexpressed a variety of tumor-related markers and remodeled the ECM. Furthermore, the metabolic signals and malignant transformation of the in vitro 3D tumor tissue was substantially similar to that observed in tumors in vivo. Conclusions: The 3D tumor tissue exhibited physiological activity with high drug resistance. The model is suitable for research studies of tumor biology and the development of personalized treatments for cancer.

Prognostic and clinicopathological value of Ki-67 expression in patients with nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: This meta-analysis aimed to identify the prognostic role of Ki-67 in patients with nasopharyngeal carcinoma (NPC). METHODS: Relevant studies were retrieved in the PubMed, Embase, Web of Science, and Cochrane Library databases up to November 2019. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to estimate the association between Ki-67 expression and survival outcomes. Combined odds ratios (ORs) and 95% CIs were measured as effect size on the association between Ki-67 expression and clinical factors. RESULTS: A total of eight studies involving 936 patients with NPC were included in this meta-analysis. The pooled HR indicated that Ki-67 expression was significantly associated with poor overall survival (HR = 2.86, 95% CI = 1.91-4.27, p < 0.001), progression-free survival (HR = 1.78, 95% CI = 1.15-2.74, p = 0.009), and distant metastasis-free survival (HR = 1.65, 95% CI = 1.15-2.36, p = 0.007). However, there was no significant correlation between Ki-67 expression and local recurrence-free survival (HR = 1.07, 95% CI = 0.54-2.14, p = 0.843). Ki-67 overexpression was associated with higher T stage (OR = 1.48, 95% CI = 1.00-2.20, p = 0.052), and the relationship between Ki-67 expression and advanced stage was nearly significant (OR = 2.25, 95% CI = 0.99-5.14, p = 0.054). However, high Ki-67 expression was not significantly correlated with sex, age, N stage, or histological type. CONCLUSION: This meta-analysis demonstrated that Ki-67 overexpression was a significant marker for poor prognosis in patients with NPC. Ki-67 should be recommended as a useful index for prognostication in patients with NPC.

Black Bioceramics: Combining Regeneration with Therapy.

Bioceramics have been developed from bioinert to bioactive or biodegradable materials in the past few decades. However, at present, traditional bioceramics are still mainly used in bone tissue regeneration and dental restoration. In this work, a new generation of "black bioceramics," extending the applications from tissue regeneration to disease therapy, is presented. Black bioceramics, through magnesium thermal reduction of traditional white ceramics, including silicate-based (e.g., CaSiO3 , MgSiO3 ) and phosphate-based (e.g., Ca3 (PO4 )2 , Ca5 (PO4 )3 (OH)), are successfully synthesized. Due to the presence of oxygen vacancies and structural defects, the black bioceramics possess photothermal functionality while maintaining their initial high bioactivity and regenerative capacity. These black bioceramics show excellent photothermal antitumor effects for both skin and bone tumors. At the same time, they have significantly improved bioactivity for skin/bone tissue repair in vitro and in vivo. These fascinating properties award the black bioceramics with profound applications in both tumor therapy and tissue regeneration, which should greatly promote the scientific relevance and clinical application of bioceramics, representing a promising new direction of cell-instructive biomaterials.