Diagnostic and prognostic significance of circulating secreted frizzled-related protein 5 in colorectal cancer.

BACKGROUND: Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC) METHODS: Plasma cSFRP5 concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in healthy donors (n = 133), individuals diagnosed with CRC (n = 449), colorectal polyps (n = 85), and medical conditions in other organs including cancer, inflammation, and benign states (n = 64). RESULTS: Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p < 0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps and CRC were 0.814 (p < 0.0001), 0.763 (p < 0.0001) and 0.762 (p < 0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p < 0.0001), tumour stage (p < 0.0001), and histological differentiation (p = 0.0273). Levels, adjusted for patient age, sex, plasma age and collection institution, peaked in stage II versus I (p < 0.0001), III (p = 0.0002) and IV (p < 0.0001), were lowest in stage I versus III (p = 0.0002) and IV (p = 0.0413), with no difference between stage III and IV. Elevated cSFRP5 levels predicted longer overall survival in stages II-III CRC (univariate: HR 1.82, 95% CI: 1.02-3.26, p = 0.024; multivariable: HR 2.34, 95% CI: 1.12-4.88, p = 0.015). CONCLUSION: This study confirms cSFRP5 levels are elevated in CRC compared to healthy control and reveals a correlation between elevated cSFRP5 and overall survival in stages II-III disease.

Identification of consensus head and neck cancer-associated microbiota signatures: a systematic review and meta-analysis of 16S rRNA and The Cancer Microbiome Atlas datasets.

Introduction. Multiple reports have attempted to describe the tumour microbiota in head and neck cancer (HNSC).Gap statement. However, these have failed to produce a consistent microbiota signature, which may undermine understanding the importance of bacterial-mediated effects in HNSC.Aim. The aim of this study is to consolidate these datasets and identify a consensus microbiota signature in HNSC.Methodology. We analysed 12 published HNSC 16S rRNA microbial datasets collected from cancer, cancer-adjacent and non-cancer tissues to generate a consensus microbiota signature. These signatures were then validated using The Cancer Microbiome Atlas (TCMA) database and correlated with the tumour microenvironment phenotypes and patient's clinical outcome.Results. We identified a consensus microbial signature at the genus level to differentiate between HNSC sample types, with cancer and cancer-adjacent tissues sharing more similarity than non-cancer tissues. Univariate analysis on 16S rRNA datasets identified significant differences in the abundance of 34 bacterial genera among the tissue types. Paired cancer and cancer-adjacent tissue analyses in 16S rRNA and TCMA datasets identified increased abundance in Fusobacterium in cancer tissues and decreased abundance of Atopobium, Rothia and Actinomyces in cancer-adjacent tissues. Furthermore, these bacteria were associated with different tumour microenvironment phenotypes. Notably, high Fusobacterium signature was associated with high neutrophil (r=0.37, P<0.0001), angiogenesis (r=0.38, P<0.0001) and granulocyte signatures (r=0.38, P<0.0001) and better overall patient survival [continuous: HR 0.8482, 95 % confidence interval (CI) 0.7758-0.9273, P=0.0003].Conclusion. Our meta-analysis demonstrates a consensus microbiota signature for HNSC, highlighting its potential importance in this disease.

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases.

Clinical application of cytokine-induced killer (CIK) cell therapy in colorectal cancer: Current strategies and future challenges.

Colorectal cancer (CRC) remains a significant global health burden and is the second leading cause of cancer-related death. Cytokine induced killer (CIK) cell therapy is an immunotherapy which has the potential to meet this need. Clinical trials of CIK cell therapy for the management of CRC have reported improved clinical outcomes. However, production and delivery protocols varied significantly, and many studies were reported only in Chinese language journals. Here we present the most comprehensive review of the clinical CIK cell therapy trials for CRC management to date. We accessed both English and Chinese language clinical studies, and summarise how CIK cell therapy has been implemented, from manufacturing to patient delivery. We discuss current challenges that impede wider adoption of CIK cell therapy in CRC management.

Use of cytokine-induced killer cell therapy in patients with colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: The number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is increasing. In many of these trials, CIK therapy was coadministered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis and to identify parameters associated with successful CIK therapy implementation. METHODS: Prospective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in patients with CRC were searched for electronically on MEDLINE, Embase, China National Knowledge Infrastructure, and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR), and toxicity were meta-analyzed using HR and relative ratio (RR), and subgroup analyses were performed using chi-square (χ2) test and I-squared (I2) statistics for study design, disease stage, cotherapy type, and timing of administration. RESULTS: In total, 70 studies involving 6743 patients were analyzed. CIK therapy was favored over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53 to 0.65), PFS (HR=0.55, 95% CI: 0.47 to 0.63), and ORR (RR=0.65, 95% CI: 0.57 to 0.74) without increasing toxicity (HR=0.59, 95% CI: 0.16 to 2.25). Subgroup analyses on OS and PFS by study design (randomized vs non-randomized study design), disease stage (Stage I-III vs Stage IV), cotreatment with dendritic cells (DCs) (CIK vs DC-CIK therapy), or timing of therapy administration (concurrent vs sequential with coadministered anticancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, cotreatment with DCs did not improve clinical outcomes over CIK therapy alone. CONCLUSION: Compared with standard therapy, patients who received additional CIK cell therapy had favorable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.

Proteomic characterisation of perhexiline treatment on THP-1 M1 macrophage differentiation.

Background: Dysregulated inflammation is important in the pathogenesis of many diseases including cancer, allergy, and autoimmunity. Macrophage activation and polarisation are commonly involved in the initiation, maintenance and resolution of inflammation. Perhexiline (PHX), an antianginal drug, has been suggested to modulate macrophage function, but the molecular effects of PHX on macrophages are unknown. In this study we investigated the effect of PHX treatment on macrophage activation and polarization and reveal the underlying proteomic changes induced. Methods: We used an established protocol to differentiate human THP-1 monocytes into M1 or M2 macrophages involving three distinct, sequential stages (priming, rest, and differentiation). We examined the effect of PHX treatment at each stage on the polarization into either M1 or M2 macrophages using flow cytometry, quantitative polymerase chain reaction (qPCR) and enzyme linked immunosorbent assay (ELISA). Quantitative changes in the proteome were investigated using data independent acquisition mass spectrometry (DIA MS). Results: PHX treatment promoted M1 macrophage polarization, including increased STAT1 and CCL2 expression and IL-1ß secretion. This effect occurred when PHX was added at the differentiation stage of the M1 cultures. Proteomic profiling of PHX treated M1 cultures identified changes in metabolic (fatty acid metabolism, cholesterol homeostasis and oxidative phosphorylation) and immune signalling (Receptor Tyrosine Kinase, Rho GTPase and interferon) pathways. Conclusion: This is the first study to report on the action of PHX on THP-1 macrophage polarization and the associated changes in the proteome of these cells.

Pt(II) metallacycles encapsulated by ferritin enable precise cancer combination chemo-photodynamic therapy.

Different from common anti-tumor drugs, organoplatinum(II) metallacycles can integrate imaging and other therapeutic capabilities by incorporating corresponding functional donor ligands to enable potential applications in biomedicine. However, most of the emerging therapeutic agents not only show poor solubility and selectivity but also have serious side effects and unsatisfactory efficacy and encounter the tendency to develop drug resistance due to their single treatment model. Herein, an organoplatinum(II) metallacycle (PtM) was designed and synthesized using coordination-driven self-assembly via the combination of a metallic chemotherapy precursor and a reactive oxygen species generating organic precursor. The hydrophobic PtM molecules were encapsulated in the cavity of human heavy chain ferritin (HFn) during the reassembly of HFn to prepare the active targeting nanoagent HFn-PtM for use in chemo-photodynamic combination therapy. The HFn-PtM nanoagents exhibited excellent stability in buffer (pH from 5 to 7.2), alleviating the concern of drug leakage during circulation. A cellular uptake assay indicated that HFn-PtM could efficiently enter specific cells that overexpress the transferrin receptor 1. In vitro and in vivo anti-tumor investigations revealed that HFn-PtM exhibited excellent anti-tumor efficiency with negligible systemic toxicity. This work provides a strategy for the easy construction of multifunctional organoplatinum-based tumor-targeted drugs.

MXenes Functionalized with Macrocyclic Hosts: From Molecular Design to Applications.

Two-dimensional (2D) MXene has aroused wide attention for its excellent physical and chemical properties. The interlayer engineering formed by layer-by-layer stacking of MXene nanosheets can be employed for molecular sieving and water purification by incorporating specific groups onto the exterior surface of MXene. Macrocyclic hosts exhibiting unique structural features and recognition ability can construct smart devices for external stimuli with reversible features between macrocycles and guests. On that basis, macrocyclic hosts can be anchored to MXene to provide numerous insights into their compositions and intercalation states. In this review, the MXene prepared based on macrocyclic hosts from molecular design to applications is highlighted. Various MXenes functionalized with macrocyclic hosts are empowered in functional membrane (including water purification, organic solvent nanofiltration, and electromagnetic shielding), photocatalysis, sensing, and adsorption (interactions with specific guest). Hopefully, this review can bring new inspiration to the design of multifunctional MXene-based materials and improving its practical applications.

Facile surface functionalization of MXene by pillar[5]arene for enhanced electrochemical performance.

A simple strategy was used to prepare functional two-dimensional materials via the combination of pillar[5]arene (P5) and MXene. The electrochemical results of MXene-P5 exhibit high supramolecular recognition, enrichment capability, and high electrochemical response toward dye molecules, which are probably due to the synergetic effects from high conductivity, high surface area, and host-guest recognition. This study provides a promising electrochemical sensing platform based on different kinds of pillararenes.

The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Perhexiline, a prophylactic anti-anginal drug, has been reported to have anti-tumour effects both in vitro and in vivo. Perhexiline as used clinically is a 50:50 racemic mixture ((R)-P) of (-) and (+) enantiomers. It is not known if the enantiomers differ in terms of their effects on cancer. In this study, we examined the cytotoxic capacity of perhexiline and its enantiomers ((-)-P and (+)-P) on CRC cell lines, grown as monolayers or spheroids, and patient-derived organoids. Treatment of CRC cell lines with (R)-P, (-)-P or (+)-P reduced cell viability, with IC50 values of ~4 µM. Treatment was associated with an increase in annexin V staining and caspase 3/7 activation, indicating apoptosis induction. Caspase 3/7 activation and loss of structural integrity were also observed in CRC cell lines grown as spheroids. Drug treatment at clinically relevant concentrations significantly reduced the viability of patient-derived CRC organoids. Given these in vitro findings, perhexiline, as a racemic mixture or its enantiomers, warrants further investigation as a repurposed drug for use in the management of CRC.

Highly Emissive Multipurpose Organoplatinum(II) Metallacycles with Contrasting Mechanoresponsive Features.

The development of supramolecular coordination complexes (SCCs) with a bright aggregate state or mechanical-stimuli-responsive luminescence is very significant and challenging. Herein, we report the synthesis of three different supramolecular platinum(II) metallacycles via coordination-driven self-assembly of a diplatinum(II) acceptor and organic donors with a triphenylamine, carbazole, or tetraphenylethylene moiety. The triphenylamine-modified SCC exhibits aggregation-induced emission enhancement (AIEE) but no mechanofluorochromism. The carbazole and tetraphenylethylene-based SCCs exhibit changes in aggregate fluorescence and also exhibit reversible mechanofluorochromism. This work not only reports three rare metallacycles with AIEE, aggregate fluorescence change, or mechanofluorochromic nature but also explores their potential applications in cell imaging and solid-state lighting.

Inorganic-Organic Hybrid Membrane Based on Pillararene-Intercalated MXene Nanosheets for Efficient Water Purification.

Discharge of antibiotic-containing wastewater causes environmental pollution and threatens biological and human health. An efficient treatment method for this wastewater is urgently required. We prepared inorganic-organic hybrid MXene-pillararene nanosheets with a large lateral size (5-8 µm). The hybrid nanosheets were stacked on supports via vacuum-assisted filtration to prepare membranes with regular parallel slits and an interlayer spacing of 1.36 nm, which were used to purify antibiotic-containing water. Permeance through the membrane increased 100-fold compared with most polymeric and other two-dimensional nanofiltration membranes with similar rejection. This high permeance and rejection was attributed to the large lateral size of the nanosheets, regular interlayer spacing, and electrostatic interaction between the membrane and antibiotics. These membranes will broaden the applications of lamellar materials for the separation of high-value-added drugs in academia and industry.

Ligand-Triggered Platinum(II) Metallacycle with Mechanochromic and Vapochromic Responses.

Supramolecular coordination complexes with solid-state stimuli-responsive characteristics are highly desirable but are rarely reported. Herein, we describe two coordination-driven self-assembled monoanthracene or dianthracene-based hexagonal metallacycles by subtle structure modification. Notably, the dianthracene-containing hexagon 1 exhibits tricolor mechanochromic and vapochromic characteristics, while the monoanthracene-containing hexagon 4 does not show obvious changes toward mechanical force. Further studies have indicated that changes in hexagon 1, especially the ulterior anthracene of hexagon 1 in the molecular stacking through intermolecular interactions toward external stimuli, are responsible for the above behavioral differences. Furthermore, the present work also demonstrates a novel light-harvesting strategy for achieving high-contrast mechanochromic fluorescence involving solid-state energy transfer from hexagon 1 to an organic carbazole derivant 6 without mechanofluorochromism or tetraphenylethylene derivant 7 exhibiting inconspicuous mechanofluorochromism.

Encapsulation of NIR-II AIEgens in Virus-like Particles for Bioimaging.

The development of organic nanoparticles that fluoresce in the near-infrared, especially in the second near-infrared (NIR-II) window, improves in vivo fluorescence imaging due to deeper penetration and higher spatiotemporal resolution. We report two kinds of NIR-II fluorescent molecules with twisted intramolecular charge-transfer (TICT) and aggregation-induced emission (AIE) characteristics. The virus-like particles (VLPs) of simian virus 40 (SV40) were used as templates to encapsulate the molecules in a well-defined structure (referred to as CH1-SV40 and CH2-SV40). The CH1-SV40 dots exhibited a highly uniform size of 21.5 nm, strong fluorescence, high photostability, and good biocompatibility in vitro and in vivo. Their fluorescence spectrum exhibited a peak at 955 nm, with a tail extending to 1200 nm. Moreover, the CH1-SV40 dots, with a quantum yield of 13.03%, enabled blood vessel imaging and image-guided surgery with a high signal-to-background ratio. Overall, the hybrid nanoparticles represent a new kind of NIR-II AIE nanoprobes for biomedical imaging.

Rhomboidal Pt(II) Metallacycle-Based Hybrid Viral Nanoparticles for Cell Imaging.

Supramolecular coordination complexes (SCCs) have emerged as anticancer agents. Tracking the movement of these metallic anticancer agents plays an important role in the field of biomedicines. Herein, we describe a method for tracking the movement of a rhomboidal Pt(II) metallacycle agent using the quantum dots encapsidation in vitro self-assembly system of viral proteins. When incubated with living Vero cells, self-assembly of hybrid viral nanoparticles were employed for simultaneous cell imaging and visual transmission of the Pt(II) metallacycle agent. Considering these results, we believe that the multifunctional biomaterials consisting of a supramolecular coordination complex and quantum dots provide a new alternative for probing of the delivery of Pt(II) metallacycle drugs.

Mechanistic Influence of Chemical Agglomeration Agents on Removal of Inhalable Particles from Coal Combustion.

Particle pollution has been a research topic attracting the attention of the researchers around the world because inhalable particles are hazardous to humans and the environment. The major resource of particle pollution is the combustion of coal and biomass. Dust collectors, electrostatic precipitators, and bag filters are required to remove particles from flue. Because of the large specific surface areas of inhalable particles, they easily agglomerate to form larger aggregates; therefore, improving the capture efficiency of dust collectors is of importance. Herein, chemical agglomeration agents were sprayed into a turbulent agglomeration chamber to improve the removal efficiency of inhalable particles. The results showed that the total removal efficiency of inhalable particles was 59.2% for the three-composition agglomeration agents of kappa carrageenans/Tween-80/NH4Cl (KC/TW/NH4Cl). The mean particle diameter increased from 2.8 µm before agglomeration to above 10.0 µm after agglomeration. In the agglomeration process, nonionic TW accelerates the wetting properties, in which the polymer, KC, or anion polyacrylamide, promotes prolongation of the contact time between droplets and particles. Two different removal mechanisms are proposed to explain the effect of chemical agglomeration agents. Immersion agglomeration described the agglomeration process of only fine particles, and distribution agglomeration supported the capture of large particles for fine ones in polydispersed aerosols.