Search

Abstract Background Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. Methods CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. Results The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. Conclusions These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.

Objectives Most functional magnetic resonance research has primarily examined alterations in the affected kidney, often neglecting the contralateral kidney. Our study aims to investigate whether imaging parameters accurately depict changes in both the renal cortex and medulla in a unilateral ureteral obstruction rat model, thereby showcasing the utility of intravoxel incoherent motion (IVIM) in evaluating contralateral renal changes.Methods Six rats underwent MR scans and were subsequently sacrificed for baseline histological examination. Following the induction of left ureteral obstruction, 48 rats were scanned, and the histopathological examinations were conducted on days 3, 7, 10, 14, 21, 28, 35, and 42. The apparent diffusion coefficient (ADC), pure molecular diffusion (D), pseudodiffusion (D*), and perfusion fraction (f) values were measured using IVIM.Results On the 10th day of obstruction, both cortical and medullary ADC values differed significantly between the UUO10 group and the sham group (p

Abstract Background Magnetic resonance imaging (MRI) can diagnose meniscal lesions anatomically, while quantitative MRI can reflect the changes of meniscal histology and biochemical structure. Our study aims to explore the association between the measurement values obtained from synthetic magnetic resonance imaging (SyMRI) and Stoller grades. Additionally, we aim to assess the diagnostic accuracy of SyMRI in determining the extent of meniscus injury. This potential accuracy could contribute to minimizing unnecessary invasive examinations and providing guidance for clinical treatment. Methods Total of 60 (n=60) patients requiring knee arthroscopic surgery and 20 (n=20) healthy subjects were collected from July 2022 to November 2022. All subjects underwent conventional MRI and SyMRI. Manual measurements of the T1, T2 and proton density (PD) values were conducted for both normal menisci and the most severely affected position of injured menisci. These measurements corresponded to the Stoller grade of meniscus injuries observed in the conventional MRI. All patients and healthy subjects were divided into normal group, degeneration group and torn group according to the Stoller grade on conventional MRI. One-way analysis of variance (ANOVA) was employed to compare the T1, T2 and PD values of the meniscus among 3 groups. The accuracy of SyMRI in diagnosing meniscus injury was assessed by comparing the findings with arthroscopic observations. The diagnostic efficiency of meniscus degeneration and tear between conventional MRI and SyMRI were analyzed using McNemar test. Furthermore, a receiver operating characteristic curve (ROC curve) was constructed and the area under the curve (AUC) was utilized for evaluation. Results According to the measurements of SyMRI, there was no statistical difference of T1 value or PD value measured by SyMRI among the normal group, degeneration group and torn group, while the difference of T2 value was statistically significant among 3 groups (P=0.001). The arthroscopic findings showed that 11 patients were meniscal degeneration and 49 patients were meniscal tears. The arthroscopic findings were used as the gold standard, and the difference of T1 and PD values among the 3 groups was not statistically significant, while the difference of T2 values (32.81±2.51 of normal group, 44.85±3.98 of degeneration group and 54.42±3.82 of torn group) was statistically significant (P=0.001). When the threshold of T2 value was 51.67 (ms), the maximum Yoden index was 0.787 and the AUC value was 0.934. Conclusions The measurement values derived from SyMRI could reflect the Stoller grade, illustrating that SyMRI has good consistency with conventional MRI. Moreover, the notable consistency observed between SyMRI and arthroscopy suggests a potential role for SyMRI in guiding clinical diagnoses.

Abstract Background Angiogenesis inhibitors have been identified to improve the efficacy of immunotherapy in recent studies. However, the delayed therapeutic effect of immunotherapy poses challenges in treatment planning. Therefore, this study aims to explore the potential of non-invasive imaging techniques, specifically intravoxel-incoherent-motion diffusion-weighted imaging (IVIM-DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), in detecting the anti-tumor response to the combination therapy involving immune checkpoint blockade therapy and anti-angiogenesis therapy in a tumor-bearing animal model. Methods The C57BL/6 mice were implanted with murine MC-38 cells to establish colon cancer xenograft model, and randomly divided into the control group, anti-PD-1 therapy group, and combination therapy group (VEGFR-2 inhibitor combined with anti-PD-1 antibody treatment). All mice were imaged before and, on the 3rd, 6th, 9th, and 12th day after administration, and pathological examinations were conducted at the same time points. Results The combination therapy group effectively suppressed tumor growth, exhibiting a significantly higher tumor inhibition rate of 69.96% compared to the anti-PD-1 group (56.71%). The f value and D* value of IVIM-DWI exhibit advantages in reflecting tumor angiogenesis. The D* value showed the highest correlation with CD31 (r = 0.702, P = 0.001), and the f value demonstrated the closest correlation with vessel maturity (r = 0.693, P = 0.001). While the BOLD-MRI parameter, R2* value, shows the highest correlation with Hif-1α(r = 0.778, P

Abstract Background The goal of this study was to create a nomogram using routine parameters to predict leptomeningeal metastases (LMs) in advanced lung adenocarcinoma (LAC) patients to prevent needless exams or lumbar punctures and to assist in accurately diagnosing LMs. Methods Two hundred and seventy‐three patients with LMs and brain metastases were retrospectively reviewed and divided into derivation (n = 191) and validation (n = 82) cohorts using a 3:7 random allocation. All LAC patients with LMs had positive cerebrospinal fluid cytology results and brain metastases confirmed by magnetic resonance imaging. Binary logistic regression with backward stepwise selection was used to identify significant characteristics. A predictive nomogram based on the logistic model was assessed through receiver operating characteristic curves. The validation cohort and Hosmer–Lemeshow test were used for internal validation of the nomogram. Results Five clinicopathological parameters, namely, gene mutations, surgery at the primary lung cancer site, clinical symptoms of the head, N stage, and therapeutic strategy, were used as predictors of LMs. The area under the curve was 0.946 (95% CI 0.912–0.979) for the training cohort and 0.861 (95% CI 0.761–0.961) for the internal validation cohort. There was no significant difference in performance between the two cohorts (p = 0.116). In the internal validation, calibration plots revealed that the nomogram predictions were well suited to the actual outcomes. Conclusions We created a user‐friendly nomogram to predict LMs in advanced lung cancer patients, which could help guide treatment decisions and reduce unnecessary lumbar punctures.

Intracranial atherosclerotic ischemic stroke dramatically impacts the quality of life among the elderly. Statins therapy has been proven to be effective in plaque stabilization and alleviation in patients with intracranial atherosclerotic ischemic stroke. According to recent studies, these effects may be directly related to lipid levels rather than specific lipid-lowering drugs. Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (PCSK-9 inhibitor) are newer effective lipid-lowering drugs increasingly prescribed to patients at high cardiovascular risk to lower LDL cholesterol. Studies have provided evidence that PCSK9 inhibitor combined with statin therapy can lead to a decrease in the plaque volume measured by intravascular ultrasound in coronary heart disease patients. But the efficacy of combination of the two drugs in symptomatic intracranial artery stenosis has been unknown. Here we provide a case which was reported to suggest that a combination of Evolocumab and intensive statin therapy might reverse or alleviate symptomatic intracranial artery stenosis.

Abstract Background Hypoxia is an important factor that contributes to chemoresistance and metastasis in triple negative breast cancer (TNBC), and alleviating hypoxia microenvironment can enhance the anti-tumor efficacy and also inhibit tumor invasion. Methods A near-infrared (NIR) responsive on-demand oxygen releasing nanoplatform (O2-PPSiI) was successfully synthesized by a two-stage self-assembly process to overcome the hypoxia-induced tumor chemoresistance and metastasis. We embedded drug-loaded poly (lactic-co-glycolic acid) cores into an ultrathin silica shell attached with paramagnetic Gd-DTPA to develop a Magnetic Resonance Imaging (MRI)-guided NIR-responsive on-demand drug releasing nanosystem, where indocyanine green was used as a photothermal converter to trigger the oxygen and drug release under NIR irradiation. Results The near-infrared responsive on-demand oxygen releasing nanoplatform O2-PPSiI was chemically synthesized in this study by a two-stage self-assembly process, which could deliver oxygen and release it under NIR irradiation to relieve hypoxia, improving the therapeutic effect of chemotherapy and suppressed tumor metastasis. This smart design achieves the following advantages: (i) the O2 in this nanosystem can be precisely released by an NIR-responsive silica shell rupture; (ii) the dynamic biodistribution process of O2-PPSiI was monitored in real-time and quantitatively analyzed via sensitive MR imaging of the tumor; (iii) O2-PPSiI could alleviate tumor hypoxia by releasing O2 within the tumor upon NIR laser excitation; (iv) The migration and invasion abilities of the TNBC tumor were weakened by inhibiting the process of EMT as a result of the synergistic therapy of NIR-triggered O2-PPSiI. Conclusions Our work proposes a smart tactic guided by MRI and presents a valid approach for the reasonable design of NIR-responsive on-demand drug-releasing nanomedicine systems for precise theranostics in TNBC. Graphical Abstract

Abstract Introduction The bilateral common carotid artery occlusion (BCCAO) rat model is an ideal animal model for simulating the pathology of chronic brain hypoperfusion in humans. However, dynamic changes in neuronal activity, cellular edema, and neuronal structural integrity in vivo after BCCAO have rarely been reported. The purpose of this study is to use a 9.4 T MRI to explore the pathophysiological mechanisms of vascular dementia. Materials and Methods Twelve Sprague–Dawley (SD) rats were randomly divided into two groups: the sham group and the model group (n = 6 for each group). Rats were subjected to MRI using T2*WI, diffusion tensor imaging (DTI), and DWI sequences by MRI at the following six time points: presurgery and 6 h, 3 days, 7 days, 21 days, and 28 days postsurgery. Then, the T2*, fractional anisotropy (FA), and average apparent diffusion coefficient (ADC) values were measured in the bilateral cortices and hippocampi. After MRI scanning, all rats in both groups were subjected to the Y‐maze test, novel object recognition test, and open‐field test to assess their learning, memory, cognition, and locomotor activity. Results The T2*, FA, and ADC values in the cerebral cortex and hippocampus decreased sharply at 6 h after BCCAO in the model group compared with those of the sham group. By Day 28, the T2* and ADC values gradually increased to close to those in the sham group, but the FA values changed little, and the rats in the model group had worse learning, memory, and cognition and less locomotor activity than the rats in the sham group. Conclusions The BCCAO is an ideal rat model for studying the pathophysiological mechanisms of vascular dementia.

Chemical exchange saturation transfer (CEST) MRI is a versatile molecular imaging approach that holds great promise for clinical translation. A number of compounds have been identified as suitable for performing CEST MRI, including paramagnetic CEST (paraCEST) agents and diamagnetic CEST (diaCEST) agents. DiaCEST agents are very attractive because of their excellent biocompatibility and potential for biodegradation, such as glucose, glycogen, glutamate, creatine, nucleic acids, et al. However, the sensitivity of most diaCEST agents is limited because of small chemical shifts (1.0–4.0 ppm) from water. To expand the catalog of diaCEST agents with larger chemical shifts, herein, we have systematically investigated the CEST properties of acyl hydrazides with different substitutions, including aromatic and aliphatic substituents. We have tuned the labile proton chemical shifts from 2.8–5.0 ppm from water while exchange rates varied from ~680 to 2340 s−1 at pH 7.2, which allows strong CEST contrast on scanners down to B0 = 3 T. One acyl hydrazide, adipic acid dihydrazide (ADH), was tested on a mouse model of breast cancer and showed nice contrast in the tumor region. We also prepared a derivative, acyl hydrazone, which showed the furthest shifted labile proton (6.4 ppm from water) and excellent contrast properties. Overall, our study expands the catalog of diaCEST agents and their application in cancer diagnosis.

Sonodynamics has emerged as a new potential therapy for breast cancer in recent years. However, GSH-mediated redox systems in cancer cells make them tolerable to oxidative stress-related therapy. Herein, in this study, with G6PD, the gatekeeper enzyme of the pentose phosphate pathway, as the regulative target, a self-assembled thermosensitive chitosan-pluronic hydrogel coloaded with ICG (sono-sensitive agent) and RRx-001 (IR@CPGel) was successfully prepared to enhance SDT through interference with redox homeostasis. Both in vitro and in vivo antitumor investigations verified that when integrated with sonodynamic therapy applied in breast cancer treatment, local administration of IR@CPgel could enhance ROS generation under LIFU irradiation and trigger the intrinsic apoptotic pathway of cancer cells, thus effectively inhibiting tumor growth in a safe manner. Moreover, RRx-001 may interfere with redox homeostasis in cancer cells by downregulating G6PD expression. Due to this redox imbalance, proapoptotic signals, such as P21 and P53, were enhanced, and metastasis-related signals, including MMP-2, ZEB1 and HIF-1α, were effectively reduced. Taken together, this work aimed to enhance the efficacy of sonodynamic therapy through local administration of self-assembled IR@CPGel to interfere with redox homeostasis and thus amplify the oxidative stress microenvironment in tumor tissues. In a word, this work provides a new strategy for the SDT enhancement in breast cancer therapy.

Angiomyofibroblastoma (AMF) is a rare benign myofibroblastic tumor that mainly occurs in the genital tract of middle-aged female patients. However, it can also arise in the scrotum, spermatic cord, and bladder. We described, herein, a case of a 42-year-old patient who was admitted to our hospital with a left scrotal mass. Imaging examinations showed that the mass had abundant vessels and displayed obvious progressive intensification on enhanced MRI. The following histopathological and immunohistochemical studies led to the diagnosis of AMF. Here, we describe the magnetic resonance imaging findings of a case of scrotal AMF. We hope that the information can help radiologists to identify AMF.

Protein PDZ and LIM domain 3 (PDLIM3) is a cytoskeletal protein, colocalizing with α-actinin on the Z line of mature muscle fibers. It plays a key role in dilated cardiomyopathy (DCM), muscular dystrophy, and tumor progression. However, correlations between PDLIM3 expression, prognosis, and tumor-infiltrating immune cells in gastric cancer are unknown. Therefore, we leveraged the Oncomine, GEPIA, GEO, and HPA databases to evaluate PDLIM3 expression in tumors. We also quantified PDLIM3 expression in 15 matched pairs of gastric tumor and nontumor tissues by immunohistochemistry. The Kaplan-Meier method was employed to determine the relationship between PDLIM3 expression and clinical outcomes. GO and KEGG analyses were performed to illuminate the molecular mechanisms of action of PDLIM3. TIMER2.0 and GEPIA were applied to investigate correlations between PDLIM3 expression and gene marker subsets signifying immune infiltration, with TIMER2.0 exploring the correlations between PDLIM3 and related signaling pathways. Gastric cancer tissues were found to express more PDLIM3 than nontumor tissues. PDLIM3 overexpression was associated with shorter OS and PFS of gastric cancer patients (OS HR=2.02, P=9.8e−10; PFS HR=1.77, P=7.5e−06). PDLIM3 was also positively correlated with worse OS and PFS according to gastric cancer staging, Her-2 overexpression, differentiation grade, and Lauren classification. PDLIM3 was shown to be associated with immunological responses by GO, while it was related to PI3K/Akt signal pathways by KEGG analysis. Furthermore, increased PDLIM3 expression was significantly correlated with greater infiltration of CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. PDLIM3 expression had significant positive correlations with a variety of immune marker subsets. Finally, correlations were found between PDLIM3 and crucial markers of signaling pathways involving PI3K/Akt and p38 MAPK. Thus, upregulation of PDLIM3 was significantly associated with poor prognosis, immune cell infiltration, and activation of two key signal pathways in gastric cancer. We propose that PDLIM3 could be used as a biomarker to predict prognosis and immune cell infiltration in gastric cancer.

Selenium nanoparticle (SeNP)-based nanotherapeutics have become an emerging cancer therapy, while effective drug delivery remains a technical hurdle. A theranostic approach, through which imaging companions are integrated with SeNPs, will allow image-guided drug delivery and, therefore, is highly desirable. Traditional methods require the chemical conjugation of imaging agents to the surface of nanoparticles, which may impede the later clinical translation. In this study, we developed a label-free strategy in which lentinan-functionalized SeNPs (LNT-SeNPs) are detected using MRI by the hydroxyl protons carried on LNT molecules. The in vitro phantom study showed that LNT and LNT-SeNPs have a strong CEST signal at 1.0 ppm apart from the water resonance, suggesting an in vivo detectability in the µM concentration range. Demonstrated on CT26 colon tumor cells, LNT-SeNPs exert a strong anticancer effect (IC50 = 4.8 μM), prominently attributed to the ability to generate intracellular reactive oxygen species. However, when testing in a mouse model of CT26 tumors, administration of LNT-SeNPs alone was found unable to deliver sufficient drugs to the tumor, leading to poor treatment responses. To improve the drug delivery, we co-injected LNT-SeNPs and TNF-α, a previously reported drug that could effectively damage the endothelial cells in the tumor vasculature, thereby increasing drug delivery to the tumor. Our results revealed a 75% increase in the intratumoral CEST MRI signal, indicating a markedly increased delivery efficiency of LNT-SeNPs when combined with TNF-α. The combination therapy also resulted in a significantly enhanced treatment outcome, as revealed by the tumor growth study. Taken together, our study demonstrates the first label-free, SeNP-based theranostic system, in which LNT was used for both functional surface coating and CEST MRI signal generating. Such a theranostic LNT-SeNP system is advantageous because it requires chemical labeling and, therefore, has high biocompatibility and low translatable barriers.

Massive reinforced concrete (MRC) structures are utilized in a variety of applications where both mechanical and thermal properties are of concern. A 1:2 large-scale test model of the steel-lined reinforced concrete penstock (a kind of MRC) and a coupled thermomechanical numerical analysis are both implemented to investigate the thermomechanical effects on structural behavior. Three different temperature fields and eight temperature gradients are selected to explore how the temperature affects the crack width, steel stress, and deformation. The results show that the numerical simulation results are consistent with the experimental results and that this method can be applied to other similar MRC structure analysis. The thermal effect can cause 10−3~10−2 mm thermal crack width and ±45 MPa thermal stress and this may lead the total crack width to exceed the limited value and the reinforcement stress beyond the yield strength. Consequently, the influence of the thermomechanical loads cannot be ignored and the corresponding temperature control measures must be taken to ensure structural safety and durability.