Development and in vitro study of a bi-specific magnetic resonance imaging molecular probe for hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)ranks second in terms of cancer mortality worldwide.Molecular magnetic resonance imaging(MRI)targeting HCC biomarkers such as alpha-fetoprotein(AFP)or glypican-3(GPC3)offers new strategies to enhance specificity and help early diagnosis of HCC.However,the existing iron oxide nanoparticle-based MR molecular probes singly target AFP or GPC3,which may hinder their efficiency to detect heterogeneous micro malignant HCC tumors<1 cm(MHCC).We hypothesized that the strategy of double antibody-conjugated iron oxide nanoparticles which simultaneously target AFP and GPC3 antigens may potentially be used to overcome the tumor heterogeneity and enhance the detection rate for MRI-based MHCC diagnosis.AIM To synthesize an AFP/GPC3 double antibody-labeled iron oxide MRI molecular probe and to assess its impact on MRI specificity and sensitivity at the cellular level.METHODS A double antigen-targeted MRI probe for MHCC anti-AFP-USPIO-anti-GPC3(UAG)was developed by simultaneously conjugating AFP andGPC3 antibodies to a 5 nm ultra-small superparamagnetic iron oxide nanoparticle(USPIO).At the same time,the singly labeled probes of anti-AFP-USPIO(UA)and anti-GPC3-USPIO(UG)and non-targeted USPIO(U)were also prepared for comparison.The physical characterization including morphology(transmission electron microscopy),hydrodynamic size,and zeta potential(dynamic light scattering)was conducted for each of the probes.The antigen targeting and MRI ability for these four kinds of USPIO probes were studied in the GPC3-expressing murine hepatoma cell line Hepa1-6/GPC3.First,AFP and GPC3 antigen expression in Hepa1-6/GPC3 cells was confirmed by flow cytometry and immunocytochemistry.Then,the cellular uptake of USPIO probes was investigated by Prussian blue staining assay and in vitro MRI(T2-weighted and T2-map)with a 3.0 Tesla clinical MR scanner.RESULTS Our data showed that the double antibody-conjugated probe UAG had the best specificity in targeting Hepa1-6/GPC3 cells expressing AFP and GPC3 antigens compared with single antibody-conjugated and unconjugated USPIO probes.The iron Prussian blue staining and quantitative T2-map MRI analysis showed that,compared with UA,UG,and U,the uptake of double antigen-targeted UAG probe demonstrated a 23.3%(vs UA),15.4%(vs UG),and 57.3%(vs U)increased Prussian stained cell percentage and a 14.93%(vs UA),9.38%(vs UG),and 15.3%(vs U)reduction of T2 relaxation time,respectively.Such bi-specific probe might have the potential to overcome tumor heterogeneity.Meanwhile,the coupling of two antibodies did not influence the magnetic performance of USPIO,and the relatively small hydrodynamic size(59.60±1.87 nm)of double antibodyconjugated USPIO probe makes it a viable candidate for use in MHCC MRI in vivo,as they are slowly phagocytosed by macrophages.CONCLUSION The bi-specific probe presents enhanced targeting efficiency and MRI sensitivity to HCC cells than singly-or non-targeted USPIO,paving the way for in vivo translation to further evaluate its clinical potential.

Diffusion magnetic resonance imaging: A molecular imaging tool caught between hope, hype and the real world of “personalized oncology”

"Personalized oncology" is a multi-disciplinary science, which requires inputs from various streams for optimal patient management. Humongous progress in the treatment modalities available and the increasing need to provide functional information in addition to the morphological data; has led to leaping progress in the field of imaging. Magnetic resonance imaging has undergone tremendous progress with various newer MR techniques providing vital functional information and is becoming the cornerstone of "radiomics/radiogenomics". Diffusionweighted imaging is one such technique which capitalizes on the tendency of water protons to diffuse randomly in a given system. This technique has revolutionized oncological imaging, by giving vital qualitative and quantitative information regarding tumor biology which helps in detection, characterization and post treatment surveillance of the lesions and challenging the notion that "one size fits all". It has been applied at various sites with different clinical experience. We hereby present a brief review of this novel functional imaging tool, with its application in "personalized oncology".

Bi-specific T1 positive-contrast-enhanced magnetic resonance imaging molecular probe for hepatocellular carcinoma in an orthotopic mouse model

BACKGROUND Hepatocellular carcinoma(HCC)is the second leading cause of cancer-related mortality.HCC-targeted magnetic resonance imaging(MRI)is an effective noninvasive diagnostic method that involves targeting clinically-related HCC biomarkers,such as alpha-fetoprotein(AFP)or glypican-3(GPC3),with iron oxide nanoparticles.However,in vivo studies of HCC-targeted MRI utilize single-target iron oxide nanoprobes as negative(T2)contrast agents,which might weaken their future clinical applications due to tumor heterogeneity and negative MRI contrast.Ultra-small superparamagnetic iron oxide(USPIO)nanoparticles(approximately 5 nm)are potential optimal positive(T1)contrast agents.We previously verified the efficiency of AFP/GPC3-double-antibody-labeled iron oxide MR molecular probe in vitro.AIM To validate the effectiveness of a bi-specific probe in vivo for enhancing T1-weighted positive contrast to diagnose the early-stage HCC.METHODS The single-and double-antibody-conjugated 5-nm USPIO probes,including antiAFP-USPIO(UA),anti-GPC3-USPIO(UG),and anti-AFP-USPIO-anti-GPC3(UAG),were synthesized.T1-and T2-weighted MRI were performed on day 10 after establishment of the orthotopic HCC mouse model.Following intravenous injection of U,UA,UG,and UAG probes,T1-and T2-weighted images were obtained at 12,12,and 32 h post-injection.At the end of scanning,mice were euthanized,and a histologic analysis was performed on tumor samples.RESULTS T1-and T2-weighted MRI showed that absolute tumor-to-background ratios in UAG-treated HCC mice peaked at 24 h post-injection,with the T1-and T2-weighted signals increasing by 46.7%and decreasing by 11.1%,respectively,relative to pre-injection levels.Additionally,T1-weighted contrast in the UAG-treated group at 24 h post-injection was enhanced 1.52-,2.64-,and 4.38-fold compared to those observed for single-targeted anti-GPC3-USPIO,anti-AFP-USPIO,and nontargeted USPIO probes,respectively.Comparison of U-,UA-,UG-,and UAG-treated tumor sections revealed that UAG-treated mice exhibited increased stained regions compared to those observed in UG-or UA-treated mice.CONCLUSION The bi-specific T1-positive contrast-enhanced MRI probe(UAG)for HCC demonstrated increased specificity and sensitivity to diagnose early-stage HCC irrespective of tumor size and/or heterogeneity.

Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease:Report of three cases

BACKGROUND Maple syrup urine disease(MSUD)is a rare autosomal-recessive disorder that affects branched-chain amino acid(BCAA)metabolism and is named after the distinctive sweet odor of affected infants’urine.This disease is characterized by the accumulation of BCAAs and corresponding branched-chain ketoacids of leucine,isoleucine,and valine in the plasma,urine,and cerebrospinal fluid.However,the mechanisms of MSUD-induced brain damage remain poorly defined.The accumulation of BCAAs in the brain inhibits the activity of pyruvate dehydrogenase andα-ketoglutarate,disrupting the citric acid cycle and consequently impacting the synthesis of amino acids,causing cerebral edema and abnormal myelination.CASE SUMMARY We report three neonates admitted to our hospital with the classic subtype of MSUD.All three patients,with a transient normal period,presented with poor feeding,vomiting,poor weight gain,and increasing lethargy after birth.Laboratory testing revealed metabolic acidosis.The serum tandem mass spectrometry amino acid profile showed elevated plasma levels of BCAAs(leucine,isoleucine,and valine).Brain magnetic resonance imaging(MRI)presented abnormal signals mainly involving the globus pallidus,thalamus,internal capsule,brainstem,and cerebellar white matter,which represent the typical myelinated areas in normal full-term neonates.CONCLUSION In our patients,MRI showed typical features,in concordance with the available literature.Early detection and timely treatment are very helpful for the prognosis of MSUD patients.Therefore,we discuss the neuroimaging features of MSUD to enhance the knowledge of pediatricians about this disease.

Diffusion tensor imaging and proton magnetic resonance spectroscopy in brain tumor Correlation between structure and metabolism

Proton magnetic resonance spectroscopy and diffusion tensor imaging are non-invasive techniques used to detect metabolites and water diffusion in vivo. Previous studies have confirmed a positive correlation of individual fractional anisotropy values with N-acetylaspartate/creatine and N-acetylaspartate/choline ratios in tumors, edema, and normal white matter. This study divided the brain parenchyma into tumor, pedtumoral edema, and normal-appearing white matter according to MRI data, and analyzed the correlation of metabolites with water molecular diffusion. Results demonstrated that in normal-appearing white matter, N-acetylaspartate/creatine ratios were positively correlated with fractional anisotropy values, negatively correlated with radial diffusivities, and positively correlated with maximum eigenvalues. Maximum eigenvalues and radial diffusivities in peritumoral edema showed a negative correlation with choline, N-acetylaspartate, and creatine. Radial diffusivities in tumor demonstrated a negative correlation with choline. These data suggest that the relationship between metabolism and structure is markedly changed from normal white matter to peritumoral edema and tumor. Neural metabolism in the peritumoral edema area decreased with expanding extracellular space. The normal relationship of neural function and microstructure disappeared in the tumor region.

In vivo imaging of structural,metabolic and functional brain changes in glaucoma

Glaucoma, the world's leading cause of irreversible blindness, is a condition for which elevated intraocular pressure is currently the only modifiable risk factor. However, the disorder can continue to progress even at reduced intraocular pressure. This indicates additional key factors that contribute to the etiopathogenesis. There has been a growing amount of literature suggesting glaucoma as a neurodegenerative disease of the visual system. However, it remains debatable whether the observed pathophysiological conditions are causes or consequences. This review summarizes recent in vivo imaging studies that helped advance the understanding of early glaucoma involvements and disease progression in the brains of humans and experimental animal models. In particular, we focused on the non-invasive detection of early structural and functional brain changes before substantial clinical visual field loss in glaucoma patients; the eye-brain interactions across disease severity; the metabolic changes occurring in the brain's visual system in glaucoma; and, the widespread brain involvements beyond the visual pathway as well as the potential behavioral relevance. If the mechanisms of glaucomatous brain changes are reliably identified, novel neurotherapeutics that target parameters beyond intraocular pressure lowering can be the promise of the near future, which would lead to reduced prevalence of this irreversible but preventable disease.

Reversible lesions in the brain parenchyma in Wilson's disease confirmed by magnetic resonance imaging:earlier administration of chelating therapy can reduce the damage to the brain

The aim of this study was to evaluate the resolution of brain lesions in patients with Wilson’s disease during the long-term chelating therapy using magnetic resonance imaging and a possible signiifcance of the time latency between the initial symptoms of the disease and the introduction of this therapy. Initial magnetic resonance examination was performed in 37 patients with proven neurological form of Wilson’s disease with cerebellar, parkinsonian and dystonic presentation. Magnetic resonance reexamination was done 5.7 ± 1.3 years later in 14 patients. Patients were divided into： group A, where chelating therapy was initiated 〈 24 months from the ifrst symp-toms and group B, where the therapy started≥ 24 months after the initial symptoms. Symmetry of the lesions was seen in 100% of patients. There was a signiifcant difference between groups A and B regarding complete resolution of brain stem and putaminal lesions （P= 0.005 andP=0.024, respectively）. If the correct diagnosis and adequate treatment are not established less than 24 months after onset of the symptoms, irreversible lesions in the brain parenchyma could be ex-pected. Signal abnormalities on magnetic resonance imaging might therefore, at least in the early stages, represent reversible myelinolisis or cytotoxic edema associated with copper toxicity.

Magnetic resonance imaging for prostate cancer clinical application

As prostate cancer is a biologically heterogeneous disease for which a variety of treatment options are available, the major objective of prostate cancer imaging is to achieve more precise disease characterization. In clinical practice, magnetic resonance imaging （MRI） is one of the imaging tools for the evaluation of prostate cancer, the fusion of MRI or dynamic contrast-enhanced MRI （DCE-MRI） with magnetic resonance spectroscopic imaging （MRSI） is improving the evaluation of cancer locafon, size, and extent, while providing an indication of tumor aggressiveness. This review summarizes the role of MRI in the application of prostate cancer and describes molecular MRI techniques （including MRSI and DCE-MRI） for aiding prostate cancer management.

Epileptic brain network mechanisms and neuroimaging techniques for the brain network

Epilepsy can be defined as a dysfunction of the brain network,and each type of epilepsy involves different brain-network changes that are implicated diffe rently in the control and propagation of interictal or ictal discharges.Gaining more detailed information on brain network alterations can help us to further understand the mechanisms of epilepsy and pave the way for brain network-based precise therapeutic approaches in clinical practice.An increasing number of advanced neuroimaging techniques and electrophysiological techniques such as diffusion tensor imaging-based fiber tra ctography,diffusion kurtosis imaging-based fiber tractography,fiber ball imagingbased tra ctography,electroencephalography,functional magnetic resonance imaging,magnetoencephalography,positron emission tomography,molecular imaging,and functional ultrasound imaging have been extensively used to delineate epileptic networks.In this review,we summarize the relevant neuroimaging and neuroelectrophysiological techniques for assessing structural and functional brain networks in patients with epilepsy,and extensively analyze the imaging mechanisms,advantages,limitations,and clinical application ranges of each technique.A greater focus on emerging advanced technologies,new data analysis software,a combination of multiple techniques,and the construction of personalized virtual epilepsy models can provide a theoretical basis to better understand the brain network mechanisms of epilepsy and make surgical decisions.

Theranostic applications:Non-ionizing cellular and molecular imaging through innovative nanosystems for early diagnosis and therapy

Modern medicine is expanding the possibilities of receiving "personalized" diagnosis and therapies,providing minimal invasiveness,technological solutions based on non-ionizing radiation,early detection of pathologies with the main objectives of being operator independent and with low cost to society.Our research activities aim to strongly contribute to these trends by improving the capabilities of current diagnostic imaging systems,which are of key importance in possibly providing both optimal diagnosis and therapies to patients.In medical diagnostics,cellular imaging aims to develop new methods and technologies for the detection of specific metabolic processes in living organisms,in order to accurately identify and discriminate normal from pathological tissues.In fact,most diseases have a "molecular basis" that detected through these new diagnostic methodologies can provide enormous benefits to medicine.Nowadays,this possibility is mainly related to the use of Positron Emission Tomography,with an exposure to ionizing radiation for patients and operators and with extremely high medical diagnosticscosts.The future possible development of non-ionizing cellular imaging based on techniques such as Nuclear Magnetic Resonance or Ultrasound,would represent an important step towards modern and personalized therapies.During the last decade,the field of nanotechnology has made important progress and a wide range of organic and inorganic nanomaterials are now available with an incredible number of further combinations with other compounds for cellular targeting.The availability of these new advanced nanosystems allows new scenarios in diagnostic methodologies which are potentially capable of providing morphological and functional information together with metabolic and cellular indications.

Magnetic resonance imaging focused on the ferritin heavy chain 1 reporter gene detects neuronal differentiation in stem cells

The neuronal differentiation of mesenchymal stem cells offers a new strategy for the treatment of neurological disorders.Thus,there is a need to identify a noninvasive and sensitive in vivo imaging approach for real-time monitoring of transplanted stem cells.Our previous study confirmed that magnetic resonance imaging,with a focus on the ferritin heavy chain 1 reporter gene,could track the proliferation and differentiation of bone marrow mesenchymal stem cells that had been transduced with lentivirus carrying the ferritin heavy chain 1 reporter gene.However,we could not determine whether or when bone marrow mesenchymal stem cells had undergone neuronal differentiation based on changes in the magnetic resonance imaging signal.To solve this problem,we identified a neuron-specific enolase that can be differentially expressed before and after neuronal differentiation in stem cells.In this study,we successfully constructed a lentivirus carrying the neuron-specific enolase promoter and expressing the ferritin heavy chain 1 reporter gene;we used this lentivirus to transduce bone marrow mesenchymal stem cells.Cellular and animal studies showed that the neuron-specific enolase promoter effectively drove the expression of ferritin heavy chain 1 after neuronal differentiation of bone marrow mesenchymal stem cells;this led to intracellular accumulation of iron and corresponding changes in the magnetic resonance imaging signal.In summary,we established an innovative magnetic resonance imaging approach focused on the induction of reporter gene expression by a neuron-specific promoter.This imaging method can be used to noninvasively and sensitively detect neuronal differentiation in stem cells,which may be useful in stem cell-based therapies.

Advancements of molecular imaging and radiomics in pancreatic carcinoma

Despite the recent progress of medical technology in the diagnosis and treatment of tumors,pancreatic carcinoma remains one of the most malignant tumors,with extremely poor prognosis partly due to the difficulty in early and accurate imaging evaluation.This paper focuses on the research progress of magnetic resonance imaging,nuclear medicine molecular imaging and radiomics in the diagnosis of pancreatic carcinoma.We also briefly described the achievements of our team in this field,to facilitate future research and explore new technologies to optimize diagnosis of pancreatic carcinoma.

What can imaging tell us about cognitive impairment and dementia?

Dementia is a contemporary global health issue with far reaching consequences, not only for affected individuals and their families, but for national and global socio-economic conditions. The hallmark feature of dementia is that of irreversible cognitive decline, usually affecting memory, and impaired activities of daily living. Advances in healthcare worldwide have facilitated longer life spans, increasing the risks of developing cognitive decline and dementia in late life. Dementia remains a clinical diagnosis. The role of structural and molecular neuroimaging in patients with dementia is primarily supportive role rather than diagnostic, American and European guidelines recommending imaging to exclude treatable causes of dementia, such as tumor, hydrocephalus or intracranial haemorrhage, but also to distinguish between different dementia subtypes, the commonest of which is Alzheimer&#x02019;s disease. However, this depends on the availability of these imaging techniques at individual centres. Advanced magnetic resonance imaging (MRI) techniques, such as functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy, and molecular imaging techniques, such as 18F fluoro-deoxy glucose positron emission tomography (PET), amyloid PET, tau PET, are currently within the realm of dementia research but are available for clinical use. Increasingly the research focus is on earlier identification of at risk preclinical individuals, for example due to family history. Intervention at the preclinical stages before irreversible brain damage occurs is currently the best hope of reducing the impact of dementia.

Lymph node imaging in initial staging of prostate cancer:An overview and update

Accurate nodal staging at the time of diagnosis of prostate cancer is crucial in determining a treatment plan for the patient. Pelvic lymph node dissection is the most reliable method, but is less than perfect and has increased morbidity. Cross sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) are non-invasive tools that rely on morphologic characteristics such as shape and size of the lymph nodes. However, lymph nodes harboring metastatic disease may be normal sized and non-metastatic lymph nodes may be enlarged due to reactive hyperplasia. The optimal strategy for preoperative staging remains a topic of ongoing research. Advanced imaging techniques to assess lymph nodes in the setting of prostate cancer utilizing novel MRI contrast agents as well as positron emission tomography (PET) tracers have been developed and continue to be studied. Magnetic resonance lymphography utilizing ultra-small super paramagnetic iron oxide has shown promising results in detection of metastatic lymph nodes. Combining MRL with diffusion-weighted imaging may also improve accuracy. Considerable efforts are being made to develop effective PET radiotracers that are performed using hybrid-imaging systems that combine PET with CT or MRI. PET tracers that will be reviewed in this article include [18F]fluoro-D-glucose, sodium [18F]fluoride, [18F]choline, [11C]choline, prostate specific membrane antigen binding ligands, [11C]acetate, [18F]fluciclovine, gastrin releasing peptide receptor ligands, and androgen binding receptors. This article will review these advanced imaging modalities and ability to detect prostate cancer metastasis to lymph nodes. While more research is needed, these novel techniques to image lymph nodes in the setting of prostate cancer show a promising future in improving initial lymph node staging.

Targeted MR Imaging Adopting T1-Weighted Ultra-Small Iron Oxide Nanoparticles for Early Hepatocellular Carcinoma:An in vitro and in vivo Study

Objective The purpose of this study was to produce an arginylglycylaspartic acid(RGD)peptide-modified ultra-small superparamagnetic iron oxide(Fe3O4)nanoparticles(NPs)for targeted magnetic resonance(MR)imaging of hepatocellular carcinoma(HCC)cells and verify its utility as aTl positive MRI imaging contrast agent in vitro and in vivo.Methods The carboxylated Fe3O4 NPs stabilized with sodium citrate were conjugated with polyethylene glycol(PEG)-linked RGD nanoparticles to form a novel target contrast agent Fe3O4-PEG-RGD NPs.The specificity of Fe3O4-PEG-RGD to bind RGD receptor was investigated in vitro by HepG2 cellular uptake and cell MR imaging,and in vivo by MR imaging of subcutaneous HepG2 tumors of nude mice.Results The formed Fe3O4-PEG-RGD NPs displayed good biocompatibility,and the ultrahigh rl relaxivity was 1.37 mM“S[The synthesized Fe3O4-PEG・RGD NPs were demonstrated sphericaLlike with an approximate diameter of 2.7 nm in similar size.The targeting effect to HepG2 cells was confirmed by in vitro cellular uptake and cell MR imaging.The in vivo MR imaging of nude mice demonstrated that the MR signal intensity enhancement of HepG2 tumor in Fe3O4-PEG-RGD NPs treated mice was significantly higher than in mice treated with non-targeted Fe3O4-mPEG NPs at the same post-administration time point.Conclusion The results indicate that the Fe3O4-PEG-RGD particles have potential utility asTl positive contrast agent in targeted MR imaging.

Tracking of Labelled Stem Cells Using Molecular MR Imaging in a Mouse Burn Model <i>in Vivo</i>as an Approach to Regenerative Medicine

Therapies based on stem cell transplants offer significant potential in the field of regenerative medicine. Monitoring the fate of the transplanted stem cells in a timely manner is considered one of the main limitations for long-standing success of stem cell transplants. Imaging methods that visualize and track stem cells in vivo non-invasively in real time are helpful towards the development of successful cell transplantation techniques. Novel molecular imaging methods which are non-invasive particularly such as MRI have been of great recent interest. Hence, mouse models which are of clinical relevance have been studied by injecting contrast agents used for labelling cells such as super-paramagnetic iron-oxide (SPIO) nanoparticles for cellular imaging. The MR techniques which can be used to generate positive contrast images have been of much relevance recently for tracking of the labelled cells. Particularly when the off-resonance region in the vicinity of the labeled cells is selectively excited while suppressing the signals from the non-labeled regions by the method of spectral dephasing. Thus, tracking of magnetically labelled cells employing positive contrast in vivo MR imaging methods in a burn mouse model in a non-invasive way has been the scope of this study. The consequences have direct implications for monitoring labeled stem cells at some stage in wound healing. We suggest that our approach can be used in clinical trials in molecular and regenerative medicine.

Relationship between magnetic resonance imaging and molecular pathology in patients with glioblastoma multiforme

Background Glioblastoma multiforme （GBM） is the most common and lethal primary brain tumor in adults. Magnetic resonance imaging （MRI） is routinely used in the diagnosis, characterization and clinical management of GBM. The diagnosis and treatment of GBM is largely guided by histopathology and immunohistochemistry. This study aimed to identify the relationship between magnetic resonance features and molecular pathology of GBM. Methods MRI images of 43 glioblastoma patients were collected. Four imaging features, degree of edema, contrast tumor enhanced/T2 ratio, multiple lesions and tumor across the midline, were selected to identify their relationship with P53, Ki-67 and O6-methylguanine-DNA methltransferase （MGMT） expression in patients with GBM. The relationship between imaging features and molecular pathology was studied by chi-square test using the software SPSS 13.0. Results High expression of P53 was found correlated with low contrast tumor enhancedFF2 ratio, low expression of Ki-67 was correlated with multiple lesions and high expression of KI-67 may be related with tumor across the midline, low expression of MGMT was correlated with edema. Conclusion Some MRI features such as the degree of edema, contrast tumor enhanced/T2 ratio, multiple lesions and tumor acrossing the midline are correlated with P53, Ki-67 and MGMT of GBM.

Label-Free Chemically and Molecularly Selective Magnetic Resonance Imaging

Biomedical imaging,especially molecular imaging,has been a driving force in scientific discovery,technological innovation,and precision medicine in the past two decades.While substantial advances and discoveries in chemical biology have been made to develop molecular imaging probes and tracers,translating these exogenous agents to clinical application in precision medicine is a major challenge.Among the clinically accepted imaging modalities,magnetic resonance imaging(MRI)and magnetic resonance spectroscopy(MRS)exemplify the most effective and robust biomedical imaging tools.Both MRI and MRS enable a broad range of chemical,biological diagnosis and characterization of many diseases and image-guided interventions.Using chemical,biological,and nuclear magnetic resonance properties of specific endogenous metabolites and native MRI contrast-enhancing biomolecules,label-free molecular and cellular imaging with MRI can be achieved in biomedical research and clinical management of patients with various diseases.This review article outlines the chemical and biological bases of several label-free chemically and molecularly selective MRI and MRS methods that have been applied in imaging biomarker discovery,preclinical investigation,and image-guided clinical management.Examples are provided to demonstrate strategies for using endogenous probes to report the molecular,metabolic,physiological,and functional events and processes in living systems,including patients.Future perspectives on label-free molecular MRI and its challenges as well as potential solutions,including the use of rational design and engineered approaches to develop chemical and biological imaging probes to facilitate or combine with label-free molecular MRI,are discussed.

同时性双侧乳腺癌分子分型与乳腺影像表现的相关性

目的分析同时性双侧乳腺癌不同分子分型与乳腺影像特征的相关性。资料与方法回顾性分析2016年1月—2022年5月青岛大学附属医院经手术病理证实的同时性双侧乳腺癌81例,其中80例接受X线检查,38例接受MRI检查。影像学特征参照第5版乳腺影像报告和数据系统。分子分型参照2013年St.Gallen国际专家共识。比较同时性双侧乳腺癌中首发癌与对侧癌的临床病理及影像表现差异以及首发癌、对侧癌不同分子分型的影像表现差异。结果首发癌与对侧癌组织学类型及分子分型差异均有统计学意义(χ^(2)=39.72、12.23,P<0.05)。X线示首发癌多为单纯肿块(51.9%,40/77),对侧癌多为单纯钙化(38.4%,28/73);首发癌多为多形性钙化(68.8%,22/32),对侧癌多为无定形钙化(45.2%,19/42)(χ^(2)=33.15、10.47,P<0.05)。MRI示首发癌与对侧癌强化方式差异有统计学意义(χ^(2)=6.79,P<0.05)。对侧癌X线示4种分子分型表现形式、肿块密度以及MRI示强化方式、早期强化程度、时间-信号强度曲线差异有统计学意义(P<0.05),对侧癌X线luminalA型多为肿块(51.3%,20/39),luminalB型(36.4%,8/22)、HER-2过表达型(50%,5/10)多为钙化,TNBC型为肿块伴钙化(χ^(2)=26.72、7.49、8.95、13.44、12.85,P<0.05)。首发癌X线示4种分子分型钙化分布差异有统计学意义(χ^(2)=20.15,P<0.05)。结论同时性双侧乳腺癌分子分型及部分影像学特征存在差异,部分影像学特征可为预测分子分型提供参考。

月经相关性偏头痛患者脑代谢的磁共振波谱研究

目的采用氢质子磁共振波谱成像研究月经相关性偏头痛(MRM)不同状态下脑代谢情况,并探讨其与临床特征及雌激素孕激素的相关性。资料与方法招募2019年4月—2022年8月河南科技大学第一附属医院神经内科门诊确诊的MRM患者36例,同时招募年龄和受教育程度相匹配的正常女性29例。采用氢质子磁共振波谱成像分别于发作间期(卵泡后期)、发作期(围月经期)检测内侧前额叶皮层(mPFC)和丘脑的主要代谢物N-乙酰天门冬氨酸、γ-氨基丁酸(GABA)、谷氨酸复合物(Glx)和胆碱(Cho)与肌酸(Cr)的比值。每次MRI成像当天同时采集静脉血检测雌激素孕激素水平。比较发作间期、发作期各脑区两组间代谢物比值及激素水平、围月经期激素下降率的差异,同时观察MRM组从发作间期到发作期脑代谢的变化。结果MRM患者较正常人卵泡后期、围月经期雌激素孕激素水平及围月经期雌激素孕激素下降率均无显著差异(P>0.05)。在发作间期,MRM组左侧mPFC Cho/Cr较对照组降低(U=-2.957,P=0.003),且与发作频率呈负相关(r=-0.398,P=0.018)。在发作期,MRM组左侧mPFC GABA/Cr较对照组降低(U=-2.015,P=0.044),左侧丘脑Glx/Cr较对照组升高(t=2.213,P=0.033),上述结果与临床特点均无显著相关性(P>0.05)。MRM患者从发作间期到发作期GABA/Cr未发生显著变化(P>0.05),而右侧丘脑Glx/Cr显著升高(t=-2.181,P=0.038),右侧丘脑Cho/Cr显著升高(Z=-2.414,P=0.016)。结论MRM患者存在与正常人不同的脑代谢情况,且伴随头痛发作存在脑代谢的变化,但本研究未发现与月经周期相关雌激素孕激素的差别,其神经机制仍需进一步研究。