Age-Related Reduction of Foot Intrinsic Muscle Function and the Relationship with Postural Stability in Old Adults.

Introduction: The risk of falls among the elderly significantly increases, which has become a serious public health concern. Falls can not only lead to serious complications such as fractures and brain injuries but also limit their mobility function, reducing quality of life. Foot intrinsic muscles (FIMs) are an essential part of foot core stability even overall postural stability. This study aimed to investigate the effects of aging on the function of FIMs and to explore the influence of FIMs on postural control in the elderly. Materials and Methods: 56 healthy old participants (60-75 years) and 57 healthy young participants (18-29 years) joined this study. An ergoFet dynamometer was used to determine foot muscle strength (Doming, T1, T23 and T2345), and ankle muscle strength (plantarflexion and dorsiflexion). The morphology of FIMs and extrinsic foot muscle was determined using a Doppler ultrasound system, whereas the postural stability was assessed through Limits of Stability test. Independent samples t-test was used to determine the differences in strength and morphological parameters and Spearman correlation analysis was used to determine whether an association existed between muscle strength and postural stability parameters in the elderly. Results: Compared with young adults, foot muscle strength and ankle muscle strength (Doming, T1, T23, T2345, dorsiflexion, and plantarflexion, all p <0.05) and the morphology of foot muscles (all p <0.05) were significantly reduced in the elderly. The strength of FIMs and the limit of stability (r = 0.302-0.424, all p <0.05) were significantly correlated in the elderly. Conclusion: Compared with young adults, the weakness of strength as well as the morphological decline of the intrinsic and extrinsic foot muscles were found in the elderly. In addition, a correlation was observed between FIM's strength and postural stability in the elderly, suggesting their potential role in posture stability.

Diagnostic accuracy of qualitative and quantitative magnetic resonance imaging-guided contrast-enhanced ultrasound (MRI-guided CEUS) for the detection of prostate cancer: a prospective and multicenter study.

PURPOSE: To evaluate the diagnostic value of MRI-guided contrast-enhanced ultrasound (CEUS) for prostate cancer (PCa) diagnosis, and characteristics of PCa in qualitative and quantitative CEUS. MATERIAL AND METHODS: This prospective and multicenter study included 250 patients (133 in the training cohort, 57 in the validation cohort and 60 in the test cohort) who underwent MRI, MRI-guided CEUS and prostate biopsy between March 2021 and February 2023. MRI interpretation, qualitative and quantitative CEUS analysis were conducted. Multitree extreme gradient boosting (XGBoost) machine learning-based models were applied to select the eight most important quantitative parameters. Univariate and multivariate logistic regression models were constructed to select independent predictors of PCa. Diagnostic value was determined for MRI, qualitative and quantitative CEUS using the area under receiver operating characteristic curve (AUC). RESULTS: The performance of quantitative CEUS was superior to that of the qualitative CEUS and MRI in predicting PCa. The AUC was 0.779 (95%CI 0.70-0.849), 0.756 (95%CI 0.638-0.874) and 0.759 (95%CI 0.638-0.879) of qualitative CEUS, and 0.885 (95%CI 0.831-0.940), 0.802 (95%CI 0.684-0.919) and 0.824 (95%CI 0.713-0.936) of quantitative CEUS in training, validation and test cohort, respectively. Compared with quantitative CEUS, MRI achieved less well performance for AUC 0.811 (95%CI 0.741-0.882, p = 0.099), 0.748 (95%CI 0.628-0.868, p = 0.539) and 0.737 (95%CI 0.602-0.873, p = 0.029), respectively. Moreover, the highest specificity of 80.6% was obtained by quantitative CEUS. CONCLUSION: We developed a reliable method of MRI-guided CEUS that demonstrated enhanced performance compared to MRI. The qualitative and quantitative CEUS characteristics will contribute to improved diagnosis of PCa.

Efficacy and safety of percutaneous ultrasound-guided thermal ablation in the treatment of cervical metastatic lymph nodes from papillary thyroid carcinoma.

OBJECTIVE: To evaluate the efficacy and safety of percutaneous ultrasound-guided thermal ablation in the treatment of cervical metastatic lymph nodes (LNs) from papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: A total of 77 patients with 79 LNs ablated by microwave ablation (MWA) or radiofrequency ablation (RFA) between September 2018 and October 2022 were enrolled in this study. After treatment, patients were followed up with measurement of diameters of LNs and serum thyroglobulin (s-Tg) at 1, 3, 6, and 12 months and annually thereafter. The paired t-test was used to compare the changes of s-Tg level, diameters of LNs before and after ablation. RESULTS: There were no serious complications related to ablation while one case of incomplete ablation in MWA was found during follow-up. The mean longest and shortest diameter of the ablated LNs reduced from 11.6 ± 4.3 mm to 5.0 ± 4.1 mm (p < 0.001), and from 6.1 ± 1.9 mm to 3.0 ± 2.5 mm (p < 0.001) at the last follow-up visit. Besides, the final volume reduction rate (VRR) was 61.8 ± 56.4% (range, -67.0 -100%). The complete disappearance rate was 46.8%, but there were 4 (5.1%) LNs becoming bigger than before. The average s-Tg level was 9.2 ± 26.6 ng/mL, a data significantly decreased to 3.7 ± 7.0 ng/mL at the last follow-up, but no statistical difference was shown. CONCLUSION: Thermal ablation is an effective and safe modality for the treatment of metastatic LNs from PTC.

Biomimetic inducer enabled dual ferroptosis of tumor and M2-type macrophages for enhanced tumor immunotherapy.

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe3+. The released Fe3+ is reduced to Fe2+ by consuming intratumoral glutathione (GSH), which promotes abundant free radical generation via triggering Fenton and Fe2+-DHA reactions, thus inducing ferroptosis of both cancer cells and M2-type TAMs. Resultantly, the anticancer immune response is strongly activated by the massive tumor-associated antigens released by ferroptositic cancer cells. Also importantly, the ferroptosis-sensitive M2-type TAMs will be either damaged or gradually domesticated to ferroptosis-resistant M1 TAMs under the ferroptosis stress, favoring the normalization of ITME and finally amplifying cancer ferroptosis immunotherapeutic efficacy. This work provides a novel strategy for ferroptosis immunotherapy of solid tumors featuring TAMs infiltration and immunosuppression by inducing dual ferroptosis of tumor cells and M2-type TAMs.

Difference in the recruitment of intrinsic foot muscles in the elderly under static and dynamic postural conditions.

Background: The effect of foot, especially intrinsic muscles, on postural control and its related mechanisms remain unclear due to the complex structure. Therefore, this study aims to investigate the activation of intrinsic foot muscles in the elderly under static and dynamic postural tasks. Methods: Twenty-one elderly participants were included to perform different postural tests (sensory organization test (SOT), motor control test (MCT), limit of stability test (LOS), and unilateral stance test) by a NeuroCom Balance Manager System. The participants were instructed to maintain postural stability under conditions with combined different sensory inputs (vision, vestibular, and proprioception) in SOT as well as conditions with translation disturbance in MCT, and to perform an active weight-shifting tasks in LOS. During these tasks, muscle activation were simultaneously acquired from intrinsic foot muscles (abductor halluces (AbH) and flexor digitorum brevis (FDB)) and ankle muscles (anterior tibialis, medial head of gastrocnemius, lateral head of gastrocnemius, and peroneus longus). The root-mean-square amplitude of these muscles in postural tasks was calculated and normalized with the EMG activity in unilateral stance task. Results: The activation of intrinsic foot muscles significantly differed among different SOT tasks (p < 0.001). Post-hoc tests showed that compared with that under normal condition 1 without sensory interference, EMGs increased significantly under sensory disturbance (conditions 2-6). By contrast, compared with that under the single-sensory disturbed conditions (conditions 2-4; 2 for disturbed vision, 3 for disturbed vestibular sensation, 4 for disturbed proprioception), activation was significantly greater under the dual-sensory disturbed postural tasks (conditions 5 and 6; 5 for disturbed vision and proprioception, 6 for disturbed vestibular sensation and proprioception). In MCT, EMGs of foot muscles increased significantly under different translation speeds (p < 0.001). In LOS, moderate and significant correlations were found between muscle activations and postural stability parameters (AbH, r = 0. 355-0.636, p < 0.05; FDB, r = 0.336-0.622, p < 0.05). Conclusion: Intrinsic foot muscles play a complementary role to regulate postural stability when disturbances occur. In addition, the recruitment magnitude of intrinsic foot muscles is positively correlated with the limit of stability, indicating their contribution to increasing the limits of stability in the elderly.

Effectiveness and Accuracy of MRI-Ultrasound Fusion Targeted Biopsy Based on PI-RADS v2.1 Category in Transition/Peripheral Zone of the Prostate.

BACKGROUND: MRI-ultrasound fusion targeted biopsy (MRI-TBx) improves the clinically significant prostate cancer (csPCa) detection with fewer cores. However, whether systematic biopsy-guided by transrectal ultrasound (TRUS-SBx) can be omitted when undergoing MRI-TBx in transition zone (TZ) and peripheral zone (PZ) remains unclear. PURPOSE: To assess the performance and effectiveness of MRI-TBx based on PI-RADS v2.1 for csPCa diagnosis in TZ and PZ, respectively. STUDY TYPE: Retrospective. SUBJECTS: A total of 309 selected cases (median age 70 years) with 356 lesions who underwent both MRI-TBx and TRUS-SBx were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0 T, multiparametric MRI (mp-MRI) including T2-weighted turbo-spin echo imaging (T2WI), diffusion-weighted spin-echo echo planar imaging (DWI), dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging (DCE). ASSESSMENT: Mp-MRI was assessed by two radiologists using PI-RADS v2.1. The csPCa detection rates provided by MRI-TBx, TRUS-SBx and combined biopsy in TZ and PZ were calculated, respectively. STATISTICAL TESTS: McNemar test was used to compare the csPCa detection rates in TZ and PZ, respectively. The frequencies and distribution of all detected prostate cancers by different biopsy methods were also compared. P < 0.05 was considered statistically significant. RESULTS: Among 356 lesions in 309 patients, 208 (68 in TZ, 140 in PZ) were pathologically confirmed as csPCa. In TZ, there were significant differences for csPCa detection with PI-RADS 3 between combined biopsy and TRUS-SBx (23.5% vs. 15.3%), MRI-TBx (23.5% vs. 16.3%), respectively. MRI-TBx detected 23% (19/83) cases missed by TRUS-SBx in which 68% (13/19) were csPCa. In PZ, there were no statistical differences between MRI-TBx and combined biopsy with PI-RADS 3-5 (P = 0.21, 0.25, 0.07, respectively). In 9% (14/152) cases only detected by MRI-TBx, 86% (12/14) were clinically significant. Five percent (7/152) of cases only detected by TRUS-SBx were completely nonclinically significant. DATA CONCLUSION: MRI-TBx played a positive role on csPCa diagnosis in TZ, but combined biopsy might be the best choice especially in the subgroup PI-RADS 3. In PZ, MRI-TBx had an advantage over TRUS-SBx for csPCa detection. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy.

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.

Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy.

A rationally designed immunostimulant (CC@SiO2-PLG) with a photoactivatable immunotherapeutic function for synergetic tumor therapy is reported. This CC@SiO2-PLG nanoplatform comprises catalase and a photosensitizer (Ce6) co-encapsulated in a silica capsule, to which an immunostimulant is conjugated through a reactive oxygen species-cleavable linker. After accumulating in tumor tissue, CC@SiO2-PLG generates O2 to relieve tumor hypoxia and promotes the production of singlet oxygen (1O2) upon laser irradiation, resulting in not only tumor destruction but also the release of tumor-associated antigens (TAAs). Simultaneously, the linker breakage by the photoproduced 1O2 leads to the remote-controlled release of conjugated indoleamine 2,3-dioxygenase (IDO) inhibitor from CC@SiO2-PLG and consequent immunosuppressive tumor microenvironment reversion. The released TAAs in conjunction with the inhibition of the IDO-mediated tryptophan/kynurenine metabolic pathway induced a boosted antitumor immune response to the CC@SiO2-PLG-mediated phototherapy. Therefore, the growth of primary/distant tumors and lung metastases in a mouse xenograft model was greatly inhibited, which was not achievable by phototherapy alone.

Two-dimensional shear wave elastography with two different systems for the diagnosis of breast lesions.

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 receiver operating characteristic curve (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.

Ultrasound-Controlled CRISPR/Cas9 System Augments Sonodynamic Therapy of Hepatocellular Carcinoma.

Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.

Biodegradable and Excretable 2D W1.33 C i-MXene with Vacancy Ordering for Theory-Oriented Cancer Nanotheranostics in Near-Infrared Biowindow.

MXenes, a new class of two-dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. Herein, a distinct W1.33 C i-MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in-plane ordered (W2/3 Y1/3 )2 AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33 C i-MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33 C i-MXene possesses a strong predominance of near-infrared (NIR) absorbance. The constructed ultrathin W1.33 C nanosheets feature excellent photothermal-conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal-imaging properties and photothermal-ablation performance of W1.33 C-BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33 C-BSA nanosheets-induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i-MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.

Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy.

The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal-organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1 O2 )-generating MOF structures anchored with CRISPR-Cas9 systems via 1 O2 -cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1 O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1 O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.

Tyrosinase-activated prodrug nanomedicine as oxidative stress amplifier for melanoma-specific treatment.

Malignant melanoma is one of the most aggressive skin cancers, posing severe threat to human health. Tyrosinase, overexpressed in melanoma cells, is a specific in-situ weapon to augment the therapeutic efficacy of melanoma-specific treatment by in-situ accelerating the activation of anti-melanoma prodrugs. Herein, we developed a tyrosinase-triggered oxidative stress amplifier, denoted as APAP@PEG/HMnO2, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO2 nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO2 nanostructures. After tumor accumulation of APAP@PEG/HMnO2 amplifier, substantial amounts of oxygen (O2) was generated through reaction between HMnO2 and excessive H2O2 present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O2 to produce cytotoxic benzoquinone metabolites (AOBQ). On the basis of the combinational effect of AOBQ-triggered reactive oxygen species (ROS) generation and synergistic glutathione (GSH) depletion as promoted by HMnO2 and AOBQ, the APAP@PEG/HMnO2 administration augmented the therapeutic efficacy of chemotherapy by amplifying the intratumoral oxidative stress, thus inducing remarkable cell apoptosis in vitro and tumor suppression in vivo. Therefore, the constructed prodrug nanomedicine represents a prospective tumor-specific therapeutic nanoagent for melanoma treatment.

In situ phase-changeable 2D MXene/zein bio-injection for shear wave elastography-guided tumor ablation in NIR-II bio-window.

Localized tumor photothermal cancer ablation is a minimally invasive therapeutic modality for combating cancer, but it often suffers from low therapeutic efficacy and poor precision due to the poor accumulation and non-uniform distribution of used photothermal-conversion agents in tumor tissue via the typical intravenous administration. To address this, an injectable and phase-changeable composite bio-injection consisting of biocompatible two-dimensional (2D) niobium carbide (Nb2C) MXene and the plant-originating protein, zein, has been engineered for near infrared (NIR)-II-triggered tumor photothermal ablation. Zein can respond to aqueous microenvironments and also external photo-triggers from the NIR-II bio-window (1064 nm), and transforms into a solid bio-implant after solvent exchange between ethanol and water. Which, thus, traps Nb2C MXene and heat, improving ablation efficiency and enabling the precise and complete eradication of 4T1 breast tumor cells without additional safety concerns. More significantly, shear wave elastography (SWE) as a deep-penetration imaging mode that can reflect the ablated outcomes via monitoring tissue density variation, has been employed to guide the photo-thermal ablation process to further improve the ablation precision. Thus, this compatible and phase-changeable bio-injection capable of improving photo-thermal ablation efficiency holds great potential in clinical applications.

Nanomedicine-Enabled Photonic Thermogaseous Cancer Therapy.

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.

Extravascular gelation shrinkage-derived internal stress enables tumor starvation therapy with suppressed metastasis and recurrence.

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.

Checkpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice.

Combined checkpoint blockade (e.g., PD1/PD-L1) with traditional clinical therapies can be hampered by side effects and low tumour-therapeutic outcome, hindering broad clinical translation. Here we report a combined tumour-therapeutic modality based on integrating nanosonosensitizers-augmented noninvasive sonodynamic therapy (SDT) with checkpoint-blockade immunotherapy. All components of the nanosonosensitizers (HMME/R837@Lip) are clinically approved, wherein liposomes act as carriers to co-encapsulate sonosensitizers (hematoporphyrin monomethyl ether (HMME)) and immune adjuvant (imiquimod (R837)). Using multiple tumour models, we demonstrate that combining nanosonosensitizers-augmented SDT with anti-PD-L1 induces an anti-tumour response, which not only arrests primary tumour progression, but also prevents lung metastasis. Furthermore, the combined treatment strategy offers a long-term immunological memory function, which can protect against tumour rechallenge after elimination of the initial tumours. Therefore, this work represents a proof-of-concept combinatorial tumour therapeutics based on noninvasive tumours-therapeutic modality with immunotherapy.

Three-dimensional shear wave elastography for differentiation of breast lesions: An initial study with quantitative analysis using three orthogonal planes.

OBJECTIVES: To prospectively evaluate the diagnostic performance of three-dimensional (3D) shear wave elastography (SWE) for breast lesions with quantitative stiffness information from transverse, sagittal and coronal planes. METHODS: Conventional ultrasound (US), two-dimensional (2D)-SWE and 3D-SWE were performed for 122 consecutive patients with 122 breast lesions before biopsy or surgical excision. Maximum elasticity values of Young's modulus (Emax) were recorded on 2D-SWE and three planes of 3D-SWE. Area under the receiver operating characteristic curve (AUC), sensitivity and specificity of US, 2D-SWE and 3D-SWE were evaluated. Two combined sets (i.e., BI-RADS and 2D-SWE; BI-RADS and 3D-SWE) were compared in AUC. Observer consistency was also evaluated. RESULTS: On 3D-SWE, the AUC and sensitivity of sagittal plane were significantly higher than those of transverse and coronal planes (both P < 0.05). Compared with BI-RADS alone, both combined sets had significantly (P < 0.05) higher AUCs and specificities, whereas, the two combined sets showed no significant difference in AUC (P > 0.05). However, the combined set of BI-RADS and sagittal plane of 3D-SWE had significantly higher sensitivity than the combined set of BI-RADS and 2D-SWE. CONCLUSIONS: The sagittal plane shows the best diagnostic performance among 3D-SWE. The combination of BI-RADS and 3D-SWE is a useful tool for predicting breast malignant lesions in comparison with BI-RADS alone.

Two-dimensional shear wave elastography for differential diagnosis between mastitis and breast malignancy.

OBJECTIVE: To determine the diagnostic performance of conventional ultrasound (US) and two-dimensional shear wave elastography (2D SWE) in the differential diagnosis between mastitis and breast malignancy. METHODS: Between January 2016 and March 2017, 105 patients with 105 pathologically proven breast lesions were enrolled. All the lesions were subject to conventional US and 2D SWE examinations. In 2D SWE, the qualitative parameter of stiff rim sign and quantitative parameter of maximal shear wave velocity (SWV) were obtained. The diagnosis performances of US and combination of US and 2D SWE were evaluated, including sensitivity, specificity and the area under the receiver operating characteristic curve (AUROC). The AUROC of US and the combined method were also evaluated in subgroups with different diameters. RESULTS: Pathologically, 26 breast lesions were confirmed to be mastitis and 79 were malignant. The cut-off value for maximal SWV was 6.75 m/sec. The AUROC of stiff rim sign and maximal SWV were 0.701 (95% CI: 0.587-0.815) and 0.753 (95% CI: 0.659-0.832) respectively. Compared with US, the specificity and AUROC of the combined method increased significantly (specificity: 11.5% vs. 96.1%, AUROC: 0.520 vs. 0.752; both P < 0.05). CONCLUSIONS: The combination of US and 2D SWE improved the diagnostic performance in the differential diagnosis between mastitis and breast malignancy in comparison with the conventional US alone.

Value of shear wave arrival time contour display in shear wave elastography for breast masses diagnosis.

To evaluate the diagnostic performance of shear wave arrival time contour (SWATC) display for the diagnosis of breast lesions and to identify factors associated with the quality of shear wave propagation (QSWP) in breast lesions. This study included 277 pathologically confirmed breast lesions. Conventional B-mode ultrasound characteristics and shear wave elastography parameters were computed. Using the SWATC display, the QSWP of each lesion was assigned to a two-point scale: score 1 (low quality) and score 2 (high quality). Binary logistic regression analysis was performed to identify factors associated with QSWP. The area under the receiver operating characteristic curve (AUROC) for QSWP to differentiate benign from malignant lesions was 0.913, with a sensitivity of 91.9%, a specificity of 90.7%, a positive predictive value (PPV) of 74.0%, and a negative predictive value (NPV) of 97.5%. Compared with using the standard deviation of shear wave speed (SWSSD) alone, SWSSD combined with QSWP increased the sensitivity from 75.8% to 93.5%, but decreased the specificity from 95.8% to 89.3% (P < 0.05). SWSSD was identified to be the strongest factor associated with the QSWP, followed by tumor malignancy and the depth of the lesion. In conclusion, SWATC display may be useful for characterization of breast lesions.