Water-soluble endohedral metallofullerenes: new horizons for biomedical applications.

Endohedral metallofullerenes (EMFs) offer a safe avenue to manipulate metals important to biomedical applications such as MRI contrast, X-ray contrast, radiolabeling, radiotherapy, chemotherapy, and the control of inflammation by scavenging reactive oxygen species (ROS). Moreover, functionalizing the double bonds on the surface of EMFs modifies their solubility, supramolecular behaviour, binding, targeting characteristics, and physical properties. While most existing water-soluble derivatives possess a statistical mixture of appended functional groups, progress has been made in creating molecularly-precise derivatives with a defined number of surface functional groups, leading to potentially more nuanced control of their behaviour and properties. Further elucidation of the structure-function relationships of these materials is expected to enhance their utility in biomedical applications and possibly broaden their use in diverse areas of science and technology.

Water-Soluble Fullerene Monoderivatives for Biomedical Applications.

Monoderivatives of fullerenes functionalized with hydrophilic groups make them water soluble, while preserving the hydrophobic fullerene cage. This class of molecules have intriguing biomedical applications, including drug delivery, photodynamic therapy (PDT), antiviral and antimicrobial activity and reactive oxygen species (ROS)-scavenging abilities. In this Concept we discuss the synthesis and biomedical applications of water-soluble fullerene monoderivatives and their biological behavior based on their structures.

Structurally Defined Water-Soluble Metallofullerene Derivatives towards Biomedical Applications.

Endohedral metallofullerenes (EMFs) are excellent carriers of rare-earth element (REE) ions in biomedical applications because they preclude the release of toxic metal ions. However, existing approaches to synthesize water-soluble EMF derivatives yield mixtures that inhibit precise drug design. Here we report the synthesis of metallobuckytrio (MBT), a three-buckyball system, as a modular platform to develop structurally defined water-soluble EMF derivatives with ligands by choice. Demonstrated with PEG ligands, the resulting water-soluble MBTs show superb biocompatibility. The Gd MBTs exhibit superior T1 relaxivity than typical Gd complexes, potentially superseding current clinical MRI contrast agents in both safety and efficiency. The Lu MBTs generated reactive oxygen species upon light irradiation, showing promise as photosensitizers. With their modular nature to incorporate other ligands, we anticipate the MBT platform to open new paths towards bio-specific REE drugs.

Surgical procedures and plasma exchange for ovarian teratoma-associated anti-N-methyl D-aspartate receptor encephalitis: a case report and review of literature.

We reported a case of ovarian teratoma-associated Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis with recurrent epileptic seizures and disturbance of consciousness. Although surgical excision of the tumor remains the established standard of care, unlike other reported cases, the patient exhibited limited response to early oophorocystectomy, as well as IVIG and steroid therapy; however, a favorable response was observed with Plasma exchange (PE) initiated on postoperative day 12. Literature review revealed no definite recommended surgical extent for ovarian teratomas, and outstanding improvement in patients with anti-NMDAR encephalitis following PE. Our case raises the question regarding the optimal surgical extent for tumor resection, necessitating careful consideration when deciding between oophorectomy and adnexectomy as the preferred surgical procedure for anti-NMDAR encephalitis in female teens and adults. Furthermore, for refractory patients who fail to respond following tumor resection, PE can be performed early instead of immediately initiating second-line therapy.

Value of Presurgical 18F-FDG PET/CT Radiomics for Predicting Mediastinal Lymph Node Metastasis in Patients with Lung Adenocarcinoma.

Objective: The aim of this study was to develop an F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomic model for predicting mediastinal lymph node metastasis (LNM) in presurgical patients with lung adenocarcinoma. Methods: The study enrolled 320 patients with lung adenocarcinoma (288 internal and 32 external cases) and extracted 190 radiomic features using the LIFEx package. Optimal radiomic features to build a radiomic model were selected using the least absolute shrinkage and selection operator algorithm. Logistic regression was used to build the clinical and complex (combined radiomic and clinical variables) models. Results: Ten radiomic features were selected. In the training group, the area under the receiver operating characteristic curve of the complex model was significantly higher than that of the radiomic and clinical models [0.924 (95% CI: 0.887-0.961) vs. 0.863 (95% CI: 0.814-0.912; p = 0.001) and 0.838 (95% CI: 0.783-0.894; p = 0.000), respectively]. The sensitivity, specificity, accuracy, and positive and negative predictive values of the radiomic model were 0.857, 0.790, 0.811, and 0.651 and 0.924, respectively, which were better than that of visual evaluation (0.539, 0.724, 0.667, and 0.472 and 0.775, respectively) and PET semiquantitative analyses (0.619, 0.732, 0.697, and 0.513 and 0.808, respectively). Conclusions: 18F-FDG PET/CT radiomics showed good predictive performance for LNM and improved the N-stage accuracy of lung adenocarcinoma.

Harnessing molecular isomerization in polymer gels for sequential logic encryption and anticounterfeiting.

Using smart photochromic and luminescent tissues in camouflage/cloaking of natural creatures has inspired efforts to develop synthetic stimuli-responsive materials for data encryption and anticounterfeiting. Although many optical data-encryption materials have been reported, they generally require only one or a simple combination of few stimuli for decryptions and rarely offer output corruptibility that prevents trial-and-error attacks. Here, we report a series of multiresponsive donor-acceptor Stenhouse adducts (DASAs) with unprecedented switching behavior and controlled reversibility via diamine conformational locking and substrate free-volume engineering and their capability of sequential logic encryption (SLE). Being analogous to the digital circuits, the output of DASA gel-based data-encryption system depends not only on the present input stimulus but also on the sequence of past inputs. Incorrect inputs/sequences generate substantial fake information and lead attackers to the point of no return. This work offers new design concepts for advanced data-encryption materials that operate via SLE, paving the path toward advanced encryptions beyond digital circuit approaches.

Synthesis of [60]- and [70]Fullerene-Fused Tetrahydroquinoxaline Derivatives by Oxidative [4 + 2] Cycloaddition with Unusual Reactivity and Regioselectivity.

The oxidative [4 + 2] reaction of o-phenylenediamine-derived disulfonamides with fullerene C60 and C70 is reported, in which electron-deficient reactants showed high reactivity. The reaction of C70 exhibited unusual regioselectivity, yielding a [5,6]-adduct as the major product, which was characterized by 1H, 13C NMR and single-crystal X-ray diffraction. DFT calculations revealed the reaction is an inverse-electron-demand Diels-Alder (IEDDA) reaction, and the [5,6]-adduct of C70 is a kinetic product.

Differentiation of Parkinson's disease and Parkinsonism predominant multiple system atrophy in early stage by morphometrics in susceptibility weighted imaging.

Background and purpose: We previously established a radiological protocol to discriminate multiple system atrophy-parkinsonian subtype (MSA-P) from Parkinson's disease (PD). However, we do not know if it can differentiate early stage disease. This study aimed to investigate whether the morphological and intensity changes in susceptibility weighted imaging (SWI) of the lentiform nucleus (LN) could discriminate MSA-P from PD at early stages. Methods: We retrospectively enrolled patients with MSA-P, PD and sex- and age-matched controls whose brain MRI included SWI, between January 2015 and July 2020 at the Movement Disorder Center. Two specialists at the center reviewed the medical records and made the final diagnosis, and two experienced neuroradiologists performed MRI analysis, based on a defined and revised protocol for conducting morphological measurements of the LN and signal intensity. Results: Nineteen patients with MSA-P and 19 patients with PD, with less than 2 years of disease duration, and 19 control individuals were enrolled in this study. We found that patients with MSA- P presented significantly decreased size in the short line (SL) and corrected short line (cSL), ratio of the SL to the long line (SLLr) and corrected SLLr (cSLLr) of the LN, increased standard deviation of signal intensity (SIsd_LN, cSIsd_LN) compared to patients with PD and controls (P < 0.05). With receiver operating characteristic (ROC) analysis, this finding had a sensitivity of 89.5% and a specificity of 73.7% to distinguish MSA- P from PD. Conclusion: Compared to PD and controls, patients with MSA-P are characterized by a narrowing morphology of the posterior region of the LN. Quantitative morphological changes provide a reference for clinical auxiliary diagnosis.

Gram-scale synthesis of a covalent nanocage that preserves the redox properties of encapsulated fullerenes.

Discrete nanocages provide a way to solubilize, separate, and tune the properties of fullerenes, but these 3D receptors cannot usually be synthesized easily from inexpensive starting materials, limiting their utility. Herein, we describe the first fullerene-binding nanocage (Cage4+) that can be made efficiently on a gram scale. Cage4+ was prepared in up to 57% yield by the formation of pyridinium linkages between complemantary porphyrin components that are themselves readily accessible. Cage4+ binds C60 and C70 with large association constants (>108 M-1), thereby solubilizing these fullerenes in polar solvents. Fullerene association and redox-properties were subsequently investigated across multiple charge states of the host-guest complexes. Remarkably, neutral and singly reduced fullerenes bind with similar strengths, leaving their 0/1- redox couples minimally perturbed and fully reversible, whereas other hosts substantially alter the redox properties of fullerenes. Thus, C60@Cage4+ and C70@Cage4+ may be useful as solubilized fullerene derivatives that preserve the inherent electron-accepting and electron-transfer capabilities of the fullerenes. Fulleride dianions were also found to bind strongly in Cage4+, while further reduction is centered on the host, leading to lowered association of the fulleride guest in the case of C60 2-.

C60-ß-cyclodextrin conjugates for enhanced nucleus delivery of doxorubicin.

We demonstrate the use of water-soluble C60-ß-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene aggregates inside cells is dictated by the functionalization of the C60 cage. While both the C60 conjugates are taken up by lysosomes upon cellular entry, only the one with a hydroxylated cage rapidly escaped the lysosome. The drug delivery system (DDS) with a hydroxylated C60 cage showed significantly enhanced doxorubicin delivery to the cell nucleus, whereas the DDS with a hydrophobic C60 cage was trapped in the lysosome for a longer time and showed significantly reduced doxorubicin delivery to the nucleus. This study opens new paths towards advanced fullerene-based DDSs for small molecule drugs.

Isocyanide-Induced Annulation Leading to Cyclopento-, Methano-, and Cyclopentano-[60]Fullerene Derivatives.

The three-component annulation reactions of C60, alkyl isocyanide, and dimethyl acetylenedicarboxylate (DMAD) or unsymmetric alkynes are investigated to afford cyclopent-2-en-1-imino- and ketenimine methano-[60]fullerene derivatives, which, upon hydration in the presence of acid, yield the corresponding fullerene amides. Dimethyl 2,3-pentadienedioate, the allene counterpart of DMAD, and ethyl buta-2,3-dienoate undergo four-component annulation with C60, alkyl isocyanide, and water under similar conditions to yield cyclopentano-[60]fullerene derivatives with similar amide groups.

Unexpected Formation of Metallofulleroids from Multicomponent Reactions, with Crystallographic and Computational Studies of the Cluster Motion.

New multicomponent reactions involving an isocyanide, terminal or internal alkynes, and endohedral metallofullerene (EMF) Lu3 N@C80 yield metallofulleroids which are characterized by mass-spectrometry, HPLC, and multiple 1D and 2D NMR techniques. Single crystal studies revealed one ketenimine metallofulleroid has ordered Lu3 N cluster which is unusual for EMF monoadducts. Computational analysis, based on crystallographic data, confirm that the endohedral cluster motion is controlled by the position of the exohedral organic appendants. Our findings provide a new functionalization reaction for EMFs, and a potential facile approach to freeze the endohedral cluster motion at relatively high temperatures.

Substantia Nigra Radiomics Feature Extraction of Parkinson's Disease Based on Magnitude Images of Susceptibility-Weighted Imaging.

BACKGROUND: It is reported that radiomic features extracted from quantitative susceptibility mapping (QSM) had promising clinical value for the diagnosis of Parkinson's disease (PD). We aimed to explore the usefulness of radiomics features based on magnitude images to distinguish PD from non-PD controls. METHODS: We retrospectively recruited PD patients and controls who underwent brain 3.0T MR including susceptibility-weighted imaging (SWI). A total of 396 radiomics features were extracted from the SN of 95 PD patients and 95 non-PD controls based on SWI. Intra-/inter-observer correlation coefficients (ICCs) were applied to measure the observer agreement for the radiomic feature extraction. Then the patients were randomly grouped into training and validation sets in a ratio of 7:3. In the training set, the maximum correlation minimum redundancy algorithm (mRMR) and the least absolute shrinkage and selection operator (LASSO) were conducted to filter and choose the optimized subset of features, and a radiomics signature was constructed. Moreover, radiomics signatures were constructed by different machine learning models. Area under the ROC curves (AUCs) were applied to evaluate the predictive performance of the models. Then correlation analysis was performed to evaluate the correlation between the optimized features and clinical factors. RESULTS: The intro-observer CC ranged from 0.82 to 1.0, and the inter-observer CC ranged from 0.77 to 0.99. The LASSO logistic regression model showed good prediction efficacy in the training set [AUC = 0.82, 95% confidence interval (CI, 0.74-0.88)] and the validation set [AUC = 0.81, 95% CI (0.68-0.91)]. One radiomic feature showed a moderate negative correlation with Hoehn-Yahr stage (r = -0.49, P = 0.012). CONCLUSION: Radiomic predictive features based on SWI magnitude images could reflect the Hoehn-Yahr stage of PD to some extent.

Eye movement especially vertical oculomotor impairment as an aid to assess Parkinson's disease.

AIMS: To detect abnormal eye movements in Parkinson's disease and explore its correlation with clinical characteristics and their value for diagnosis. METHODS: We recruited forty-nine Parkinson's disease patients, including 35 early Parkinson's disease patients (Hoehn-Yahr: 1 to 2 stage) and 14 advanced Parkinson's disease patients (Hoehn-Yahr: 3 to 5 stage) and 23 healthy controls. Clinical manifestations in Parkinson's disease patients were recorded. Oculomotor performances including fixation, gaze, saccade in horizontal and vertical direction, and smooth pursuit in horizontal and vertical direction were measured by video-oculography. RESULTS: We found that five oculomotor parameters, namely square wave jerk frequency, latency of downward saccade, latency of upward saccade, accuracy of upward saccade, and gain of horizontal smooth pursuit were significantly different in Parkinson's disease patients and controls. When combining all these five parameters, we got the diagnostic sensitivity of 78.3% and specificity of 95.2%. More deficits in upward saccade than in other directions were associated with disease duration and progression of Parkinson's disease. CONCLUSION: Our primary study suggests that oculomotor examination might serve as an aid in the clinical assessment of Parkinson's disease patients and differentiating between early Parkinson's disease and normal controls.

Value of 18F-FDG PET/CT radiomic features to distinguish solitary lung adenocarcinoma from tuberculosis.

PURPOSE: To develop a predictive model by 18F-FDG PET/CT radiomic features and to validate the predictive value of the model for distinguishing solitary lung adenocarcinoma from tuberculosis. METHODS: A total of 235 18F-FDG PET/CT patients with pathologically or follow-up confirmed lung adenocarcinoma (n = 131) or tuberculosis (n = 104) were retrospectively and randomly divided into a training (n = 163) and validation (n = 72) cohort. Based on the Transparent Reporting of Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), this work was belonged to TRIPOD type 2a study. The Mann-Whitney U test and least absolute shrinkage and selection operator (LASSO) algorithm were used to select the optimal predictors from 92 radiomic features that were extracted from PET/CT, and the optimal predictors were used to build the radiomic model in the training cohort. The meaningful clinical variables comprised the clinical model, and the combination of the radiomic model and clinical model was a complex model. The performances of the models were assessed by the area under the receiver operating characteristic curve (AUC) in the training and validation cohorts. RESULTS: In the training cohort, 9 radiomic features were selected as optimal predictors to build the radiomic model. The AUC of the radiomic model was significantly higher than that of the clinical model in the training cohort (0.861 versus 0.686, p < 0.01), and this was similar in the validation cohort (0.889 versus 0.644, p < 0.01). The AUC of the radiomic model was slightly lower than that of the complex model in the training cohort (0.861 versus 0.884, p > 0.05) and validation cohort (0.889 versus 0.909, p > 0.05), but there was no significant difference. CONCLUSION: 18F-FDG PET/CT radiomic features have a significant value in differentiating solitary lung adenocarcinoma from tuberculosis.

Morphology and signal changes of the lentiform nucleus based on susceptibility weighted imaging in parkinsonism-predominant multiple system atrophy.

INTRODUCTION: It remains challenging to make a differential diagnosis between atypical parkinsonism and Parkinson's disease (PD) from routine neuroimaging. This case-control study aimed to quantitatively investigate both morphological and signal intensity changes in susceptibility weighted imaging (SWI) of the lentiform nucleus (LN) for discriminating parkinsonism-predominant multiple system atrophy (MSA-P) from PD. METHODS: We retrospectively enrolled patients with MSA-P, PD, and sex- and age-matched controls between January 2016 and November 2019 at the Movement Disorder Center who underwent 3T MR imaging of brain with SWI sequence. Two specialists at the center reviewed the medical records and made the final diagnosis, and two experienced neuroradiologists performed MRI image analysis based on a defined radiological protocol to conduct the ROI-based morphological measurements of the LN and the signal intensity. RESULTS: A total of 19 patients with MSA-P, 19 patients with PD and 19 controls were enrolled in this study. We found that patients with MSA-P had significant decreases size in the short line (SL) and the ratio of the SL and the long line (SLLr) and increased value in the signal intensity standard deviation of the LN (SIsd_LN) compared with the patients with PD and with the controls (P < 0.05). Combining these three indexes, this finding had a sensitivity of 94.7% and a specificity of 63.2% to distinguish MSA-P from PD. CONCLUSION: As compared to PD and control subjects, the SA-P patients are characterized by narrowing morphology and the inhomogeneous signal intensity of the posterior region of LN. The quantitative morphological change is a possible potential marker to differentiate MSA-P from PD on SWI.

Non-invasive decision support for NSCLC treatment using PET/CT radiomics.

Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments.

Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson's disease.

Catechol-O-methyltransferase (COMT) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to Parkinson's disease (PD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in Chinese PD patients. Eleven single nucleotide polymorphisms (SNPs) in the COMT gene were genotyped, and clinical data were collected. Patients with the TT genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and CT genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with TT and TC (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation.