Yan Fang's research while affiliated with Tongji University and other places

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor‐associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co‐deliver a tumor‐associated antigen (TAA) encoded by the Wilms' tumor 1 ( WT1 ) mRNA. In this system, named PSB@Nb 1.33 C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the i MXene‐ WT1 mRNA to the core tumor region using photo‐driven and hypoxia‐driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D i Mxene (Nb 1.33 C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo‐immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

Reprogramming the tumor immunosuppressive microenvironment is a promising strategy for improving tumor immunotherapy efficacy. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 system can be used to knockdown tumor immunosuppression-related genes. Therefore, here, a self-driven multifunctional delivery vector is constructed to efficiently deliver the CRISPR-Cas9 nanosystem for indoleamine 2,3-dioxygenase-1 (IDO1) knockdown in order to amplify immunogenic cell death (ICD) and then reverse tumor immunosuppression. Lactobacillus rhamnosus GG (LGG) is a self-driven safety probiotic that can penetrate the hypoxia tumor center, allowing efficient delivery of the CRISPR/Cas9 system to the tumor region. While LGG efficiently colonizes the tumor area, it also stimulates the organism to activate the immune system. The CRISPR/Cas9 nanosystem can generate abundant reactive oxygen species (ROS) under the ultrasound irradiation, resulting in ICD, while the produced ROS can induce endosomal/lysosomal rupture and then releasing Cas9/sgRNA to knock down the IDO1 gene to lift immunosuppression. The system generates immune responses that effectively attack tumor cells in mice, contributing to the inhibition of tumor re-challenge in vivo. In addition, this strategy provides an immunological memory effect which offers protection against lung metastasis. Recently, strategies based on the integration of nanotechnology with microbial carriers have been proposed for cancer therapy. Here the authors report the design of an ultrasound-controlled CRISPR/Cas9 gene editing system for IDO1 silencing compounded with the probiotic Lactobacillus rhamnosus GG, showing the induction of anti-tumor immune responses in preclinical cancer models.

Continuous assessment of disease activity remains a huge challenge during the follow-ups of patients with Crohn’s disease (CD). In this paper, we aimed to evaluate the performance of contrast-enhanced ultrasound (CEUS) by comparing with computed tomography enterography (CTE) in the assessment of disease activity in CD. Fifty-two patients diagnosed with CD were included in this study, using the CEUS and CTE as imaging methods for comparison. The selected parameters included the location and thickness of the thickest part of the intestinal wall, mesenteric fat proliferation, mesenteric vessels change, enhancement pattern and the presence of complications. Patients were clinically assessed using the Crohn's disease activity index (CDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Simple endoscopic score for Crohn’s disease (SES-CD) was regarded as the reference standard. The location of the thickest part of the intestinal wall (κ = 0.653), bowel wall thickness (ICC = 0.795), mesenteric vessels change (κ = 0.692) and complications (κ = 0.796) displayed substantial agreement (0.61–0.80) between CEUS and CTE, while the detection of mesenteric fat proliferation (κ = 0.395) and enhancement pattern (κ = 0.288) showed fair consistency (0.21–0.40) for comparison. In CEUS, bowel wall thickness, mesenteric fat proliferation, enhancement pattern and mesenteric vessels change were statistically significant in assessing CD activity, while bowel wall thickness, mesenteric fat proliferation and mesenteric vessels change in CTE. Bowel wall thickness showed the best diagnostic performance in the assessment of CD activity at CEUS and CTE. CEUS provides a radiation-free and effective way to assess the CD activity in comparison with CTE, which also avoids frequent colonoscopy examinations, improves tolerance of patients, and reduces the cost of medical care, thereby serving as a useful tool for CD follow-up.

Background: Two-dimensional (2D) - shear wave elastography (SWE) has made promising advances in the diagnostic of breast lesions. However, few studies have assessed whether the diagnostic effectiveness of different platforms employing 2D-SWE is equal or different. Objective: To compare the diagnostic effectiveness of 2D-SWE techniques from two different systems in differentiating malignant breast lesions from benign ones. Methods: A total of 84 breast lesions were retrospectively analyzed by experienced radiologists using 2D-SWE on two ultrasound systems, i.e. system-1 (LOGIQ E9 system, GE Healthcare, Wauwatosa, WI, USA), and system-2 (Aixplorer US system, SuperSonic Imagine, Aix-en-Provence, France). Qualitative and quantitative parameters including color sign, the maximum elasticity modulus values (E-max), the mean elasticity modulus values (E-mean) and standard deviation (E-sd) of elasticity modulus values in two 2D-SWE systems were analyzed. The diagnostic performance between system-1 and system-2 were evaluated in terms of the areas under the receiver operating characteristic curves (AUROCs). Results: Among the 84 lesions in this study, 66 (78.6%) were benign and 18 (21.4%) were malignant. E-max in system-1 showed the best diagnostic performance with a cut-off value of 174.5 kPa with the associated sensitivity and specificity of 100.0% and 80.3% respectively. Meanwhile, E-sd in system-2 displayed the best diagnostic performance with a cut-off value of 12.7 kPa, with the associated sensitivity and specificity of 94.4% and 80.3% respectively. The diagnostic performance of the two 2D-SWE systems was not statistically different according to ROC analysis of E-max, E-mean, and E-sd. Conclusion: For identifying breast lesions, system-1 and system-2 appear to be similar in diagnostic performance. However, different cut-off values for different parameters might be selected to obtain the best diagnostic performance for the two 2D-SWE systems.

The purpose of this study was to evaluate the diagnostic performance of multiparametric ultrasound (mpUS; grayscale US, color Doppler US, strain elastography, and contrast-enhanced US) in the assessment of testicular lesions with negative tumoral markers. MpUS imaging data, patient age, serum tumor markers, scrotal pain, cryptorchidism, and related clinical information were retrospectively collected for patients who underwent mpUS examination between January 2013 and December 2019. Histologic results or follow-up examinations were used as the reference standard. In total, 83 lesions from 79 patients were included in the analysis. Fifty-six patients were finally diagnosed with benign tumors, and 23 patients were ultimately diagnosed with malignant tumors. Chi-square tests or Fisher's exact tests were used to assess the difference between the two groups. Stepwise multivariate logistic regression analysis showed that lesion diameter (odds ratio [OR] = 1.072, P = 0.005), vascularization on color Doppler US (OR = 4.066, P = 0.001), and hyperenhancement during the early phase (OR = 6.465, P = 0.047) were significant independent risk factors for malignancy; however, when compared with neoplastic lesions, pain (OR = 0.136, P < 0.001), absence of vascularization on color Doppler US (OR = 1.680, P = 0.042), and nonenhancement during the late phase (OR = 3.461, P = 0.031) were strongly associated with nonneoplastic lesions. MpUS features are useful for differentiating testicular lesions with negative tumoral markers and improving the preoperative diagnosis, which may avoid inappropriate radical orchiectomy.

Abstract Local photothermal hyperthermia for tumor ablation and specific stimuliresponsive gas therapy feature the merits of remote operation, noninvasive intervention, and in situ tumor‐specific activation in cancer‐therapeutic biomedicine. Inspired by synergistic/sequential therapeutic modality, herein a novel therapeutic modality is reported based on the construction of two‐dimensional (2D) core/shell‐structured Nb2C–MSNs–SNO composite nanosheets for photonic thermogaseous therapy. A phototriggered thermogas‐generating nanoreactor is designed via mesoporous silica layer coating on the surface of Nb2C MXene nanosheets, where the mesopores provide the reservoirs for NO donor (S‐nitrosothiol (RSNO)), and the core of Nb2C produces heat shock upon second near‐infrared biowindow (NIR‐II) laser irradiation. The Nb2C–MSNs–SNO‐enabled photonic thermogaseous therapy undergoes a sequential process of phototriggered heat production from the core of Nb2C and thermotriggered NO generation, together with photoacoustic‐imaging (PAI) guidance and monitoring. The constructed Nb2C–MSNs–SNO nanoreactors exhibit high‐NIR‐induced photothermal effect, intense NIR‐controlled NO release, and desirable PAI performance. Based on these unique theranostic properties of Nb2C–MSNs–SNO nanocomposites, sequential photonic thermogaseous therapy with limited systematic toxicity on efficiently suppressing tumor growth is achieved by PAI‐guided NIR‐controlled NO release as well as heat generation. Such a thermogaseous approach representes a stimuli‐selective strategy for synergistic/sequential cancer treatment.

Despite the efficacy of current starvation therapies, they are often associated with some intrinsic drawbacks such as poor persistence, facile tumor metastasis and recurrence. Herein, we establish an extravascular gelation shrinkage-derived internal stress strategy for squeezing and narrowing blood vessels, occluding blood & nutrition supply, reducing vascular density, inducing hypoxia and apoptosis and eventually realizing starvation therapy of malignancies. To this end, a biocompatible composite hydrogel consisting of gold nanorods (GNRs) and thermal-sensitive hydrogel mixture was engineered, wherein GRNs can strengthen the structural property of hydrogel mixture and enable robust gelation shrinkage-induced internal stresses. Systematic experiments demonstrate that this starvation therapy can suppress the growths of PANC-1 pancreatic cancer and 4T1 breast cancer. More significantly, this starvation strategy can suppress tumor metastasis and tumor recurrence via reducing vascular density and blood supply and occluding tumor migration passages, which thus provides a promising avenue to comprehensive cancer therapy. The efficacy of tumour starvation therapy is limited by lack of persistent tumour suppression, tumour metastasis and recurrence. Here, the authors report biocompatible gold nanorods and thermal-sensitive hydrogel to promote narrowing of blood vessels and show this to reduce tumour growth and metastasis.

Low quantum yield and aggregation‐mediated quenching are two concerns for fluorescence imaging. However, there are not yet general means available for addressing these issues. Herein, a viscosity confinement‐mediated antiaggregation strategy is established to enable the improved fluorescence properties of entrapped fluorophores in dye‐encapsulation nanotechnology including quantum yield, fluorescence lifetime, and photostability. To instantiate this strategy, solid DL‐menthol (DLM) is introduced to disperse entrapped indocyanine green (ICG) fluorophores when coencapsulating DLM and ICG molecules in organic poly(lactic‐co‐glycolic acid) carriers. Depending on the robust ability of highly viscous DLM to augment the migration barrier and diminish diffusion coefficient, ICG aggregation and aggregation‐mediated quenching are demonstrated to be theoretically and experimentally inhibited, resulting in prolonged fluorescence lifetime, increased quantum yield, and facilitated radiative process. Consequently, the fluorescence imaging ability and photostability are significantly improved, enabling the in vitro, cellular‐level, and in vivo fluorescence imaging. More significantly, this solid DLM‐mediated antiaggregation strategy can act as a general method to extend to the intermolecular fluorescence resonance energy transfer (FRET) process and improve FRET efficiency via inhibiting the aggregation‐mediated quenching. Solid DL‐menthol is introduced into poly(lactic‐co‐glycolic acid) carriers to disperse entrapped fluorophores and established viscosity confinement‐mediated antiaggregation strategy for inhibiting quenching and improving fluorescence imaging properties associated with quantum yield, fluorescence lifetime, and photostability via the high viscosity‐mediated migration barrier elevation, which provides a new avenue to improving fluorescence imaging of entrapped fluorophores in dye‐encapsulation nanotechnology.

Our study aimed to investigate the correlation of the imaging features obtained using conventional ultrasound (US) and elastography (conventional strain elastography of elasticity imaging [EI], virtual touch tissue imaging [VTI] and 2-D shear wave elastography [2-D-SWE] of virtual touch tissue imaging quantification [VTIQ]) with the clinicopathologic features and immunohistochemical (IHC) subtypes of breast cancer. The sample consisted of images from 202 patients with 206 breast lesions that were confirmed as breast cancers. Lesions with HER2 overexpression (luminal B HER2+ or HER2+) had higher mean shear wave velocity (SWV) values than the others. Older patients, lower histologic grade, no lymphovascular invasion and no lymph node metastasis were associated with luminal A (p < 0.001). There were significant differences in SWV values, histologic grade and lymph node status among the different pathologic types. This association may allow the use of 2-D-SWE in the pre-operative prediction of tumor characteristics and biologic activity, which may determine the prognosis in a non-invasive manner.

Objectives To analyze the diagnostic value of adding SWE to MRI for the diagnosis of clinically significant prostate cancer with false-negative MRI results. Methods This was a retrospective study of 367 patients who underwent MRI, SWE, and prostate biopsy between March 2016 and November 2018 at the Shanghai Tenth People’s Hospital. Serum prostate-specific antigen (PSA) and free PSA (fPSA) were measured preoperatively. Diagnostic value and accuracy was determined for MRI alone and MRI + SWE using the receiver operator characteristic curve (ROC) analysis. Results MRI misdiagnosed 17.9% (21/117) clinically significant prostate cancers, including 15 lesions in the peripheral zone and 6 in the central zone. Both qualitative and quantitative SWE could help detect 66.7% (10/15) significant prostate cancers with false-negative MRI, but there was no association with the Gleason score (p > 0.05). When considering the sextant of the peripheral zone, a significant association was not seen with histopathology in qualitative SWE (p = 0.071) and quantitative SWE (p = 0.598). Among age, PSA, fPSA, volume of the prostate gland, fPSA/PSA, and PSAD, only PSAD (p = 0.019) was associated with SWE results in patients with negative MRI. Conclusions Adding SWE to MRI in patients with negative MRI for prostate examination could allow the correct diagnosis of additional patients and reduce the false-negative rate. Key Points • MRI plays an important role in clinically significant prostate cancers diagnosis. • SWE plays an important role in clinically significant prostate cancers with negative MRI. • Adding SWE to MRI in patients with negative MRI for prostate examination could allow the correct diagnosis of additional patients and reduce the false-negative rate.