FXR suppresses colorectal cancer by inhibiting the Wnt/β-catenin pathway via activation of TLE3

Colorectal cancer(CRC)is the third most common and lethal cancer worldwide.1 Farnesoid X receptor(FXR)is a regulator of bile acid(BA)homeostasis and its expression is inversely correlated with the incidence of CRC.2,3 Moreover,our recent study discovered that dietary factors and dysregulated Wnt signaling independently alter BA profiles,some of which antagonize intestinal FXR,such as Tauro-β-muricholic acid(T-βMCA)and deoxycholic acid(DCA).

Network analyses:Inhibition of androgen receptor signaling reduces inflammation in the lung through AR-MAF-IL6 signaling axes

Androgen receptor(AR)is a major transcription factor that plays a role in inflammatory response including interleukin-6(IL6)signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied,its impact through an IL6 autocrine loop in the lung has not been wellstudied despite the organ's response to respiratory viral infection.Chemical inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells.

In vitro study of enhanced photodynamic cancer cell killing effect by nanometer-thick gold nanosheets

Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.

In Vivo Tumor-Targeted Dual-Modality PET/Optical Imaging with a Yolk/Shell-Structured Silica Nanosystem

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic outcomes.By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

Nanostructured polyvinylpyrrolidone-curcumin conjugates allowed for kidney-targeted treatment of cisplatin induced acute kidney injury

Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.

General synthesis of silica-based yolk/shell hybrid nanomaterials and in vivo tumor vasculature targeting

Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 （89Zr）-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/sheU hybrid nanopartides for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanosheUs to form the yolk/sheU-structured hybrid nanopartides. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody （specific for CD105/endoglin）, and ~Zr （a positron-emitting radioisotope）, and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1 murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor- targeted imaging and drug delivery.

Adoptive transfer of IL-10^(+) regulatory B cells decreases myeloid-derived macrophages in the central nervous system in a transgenic amyotrophic lateral sclerosis model

I mmunosuppressive therapies have meaningful effects on the treatment of multiple sclerosis(MS),a classical inflammatory autoimmune disease of the central nervous system.1 In mice with experimental autoimmune encephalomyelitis(EAE),a murine model of human MS,we showed that an adoptive transfer of GM-CSF and Interleukin-15 Fusion Transgene(GIFT15)-derived regulatory B cells(GIFT15 Bregs)sustained a durable remission of the disease.2,3 These regulatory B cells require the expression of MHC class II and IL-10 for suppressive activity.

Microphysiological systems for solid tumor immunotherapy:opportunities and challenges

Immunotherapy remains more effective for hematologic tumors than for solid tumors.One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate,which limits the cytotoxic capabilities of immune effector cells(e.g.,cytotoxic T and natural killer cells).This microenvironment is characterized by hypoxia,nutrient starvation,accumulated waste products,and acidic pH.Tumor-hijacked cells,such as fibroblasts,macrophages,and T regulatory cells,also contribute to this inhospitable microenvironment for immune cells by secreting immunosuppressive cytokines that suppress the antitumor immune response and lead to immune evasion.Thus,there is a strong interest in developing new drugs and cell formulations that modulate the tumor microenvironment and reduce tumor cell immune evasion.Microphysiological systems(MPSs)are versatile tools that may accelerate the development and evaluation of these therapies,although specific examples showcasing the potential of MPSs remain rare.Advances in microtechnologies have led to the development of sophisticated microfluidic devices used to recapitulate tumor complexity.The resulting models,also known as microphysiological systems(MPSs),are versatile tools with which to decipher the molecular mechanisms driving immune cell antitumor cytotoxicity,immune cell exhaustion,and immune cell exclusion and to evaluate new targeted immunotherapies.Here,we review existing microphysiological platforms to study immuno-oncological applications and discuss challenges and opportunities in the field.