Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Diagnostic Superiority of 18 F-FDG PET Over MRI in Detecting Anti-LGI1 Autoimmune Encephalitis : A Comparative Study With Insights Into Faciobrachial Dystonic Seizures Mechanisms and Recurrence Identification.

OBJECTIVE: Our study aimed to investigate the utility of 18 F-FDG PET imaging in diagnosing and monitoring patients with anti-leucine-rich glioma-inactivated 1 antibody autoimmune encephalitis (anti-LGI1 AE). We also sought to understand the mechanisms of faciobrachial dystonic seizures (FBDSs). PATIENTS AND METHODS: We analyzed 18 F-FDG PET scans from 50 patients with anti-LGI1 AE, using visual and semiquantitative methods, and compared these with 24 healthy controls. All patients tested positive for anti-LGI1 antibodies in serum or cerebrospinal fluid before PET imaging. The patients were divided into FBDS and non-FBDS groups to compare metabolic differences using voxel-based semiquantitative analysis. Finally, we separately analyzed PET images of patients with symptom recurrence. RESULTS: The sensitivity of 18 F-FDG PET was superior to MRI (97.9% vs 63.8%, respectively; P < 0.001). Semiquantitative analysis revealed hypermetabolism in the basal ganglia, medial temporal lobe, and brainstem, and hypometabolism in most neocortical regions compared with healthy controls. The FBDS group exhibited hypometabolism in the frontal and temporal lobes compared with the non-FBDS group. Among 7 recurrent patients, 3 were confirmed as recurrence and 3 as sequelae by PET. One patient relapsed shortly after discontinuing corticosteroids when PET indicated active lesions. CONCLUSIONS: 18 F-FDG PET scans were more sensitive than MRI in detecting anti-LGI1 AE, which displayed a pattern of hypermetabolism in the basal ganglia and medial temporal lobe, as well as neocortex hypometabolism. Hypometabolism in the frontal and temporal lobes was associated with FBDS. Furthermore, 18 F-FDG PET scans can differentiate recurrence from sequelae and guide the timing of immunotherapy cessation.

Deep learning for predicting epidermal growth factor receptor mutations of non-small cell lung cancer on PET/CT images.

Background: Predicting the mutation status of the epidermal growth factor receptor (EGFR) gene based on an integrated positron emission tomography/computed tomography (PET/CT) image of non-small cell lung cancer (NSCLC) is a noninvasive, low-cost method which is valuable for targeted therapy. Although deep learning has been very successful in robotic vision, it is still challenging to predict gene mutations in PET/CT-derived studies because of the small amount of medical data and the different parameters of PET/CT devices. Methods: We used the advanced EfficientNet-V2 model to predict the EGFR mutation based on fused PET/CT images. First, we extracted 3-dimensional (3D) pulmonary nodules from PET and CT as regions of interest (ROIs). We then fused each single PET and CT image. The network model was used to predict the mutation status of lung nodules by the new data after fusion, and the model was weighted adaptively. The EfficientNet-V2 model used multiple channels to represent nodules comprehensively. Results: We trained the EfficientNet-V2 model through our PET/CT fusion algorithm using a dataset of 150 patients. The prediction accuracy of EGFR and non-EGFR mutations was 86.25% in the training dataset, and the accuracy rate was 81.92% in the validation set. Conclusions: Combined with experiments, the demonstrated PET/CT fusion algorithm outperformed radiomics methods in predicting EGFR and non-EGFR mutations in NSCLC.

A deep learning model based on the attention mechanism for automatic segmentation of abdominal muscle and fat for body composition assessment.

Background: Quantitative muscle and fat data obtained through body composition analysis are expected to be a new stable biomarker for the early and accurate prediction of treatment-related toxicity, treatment response, and prognosis in patients with lung cancer. The use of these biomarkers can enable the adjustment of individualized treatment regimens in a timely manner, which is critical to further improving patient prognosis and quality of life. We aimed to develop a deep learning model based on attention for fully automated segmentation of the abdomen from computed tomography (CT) to quantify body composition. Methods: A fully automatic segmentation deep learning model was designed based on the attention mechanism and using U-Net as the framework. Subcutaneous fat, skeletal muscle, and visceral fat were manually segmented by two experts to serve as ground truth labels. The performance of the model was evaluated using Dice similarity coefficients (DSCs) and Hausdorff distance at 95th percentile (HD95). Results: The mean DSC for subcutaneous fat and skeletal muscle were high for both the enhanced CT test set (0.93±0.06 and 0.96±0.02, respectively) and the plain CT test set (0.90±0.09 and 0.95±0.01, respectively). Nevertheless, the model did not perform well in the segmentation performance of visceral fat, especially for the enhanced CT test set. The mean DSC for the enhanced CT test set was 0.87±0.11, while the mean DSC for the plain CT test set was 0.92±0.03. We discuss the reasons for this result. Conclusions: This work demonstrates a method for the automatic outlining of subcutaneous fat, skeletal muscle, and visceral fat areas at L3.

Phase separation of SGS3 drives siRNA body formation and promotes endogenous gene silencing.

The generation of small interfering RNA (siRNA) involves many RNA processing components, including SUPPRESSOR OF GENE SILENCING 3 (SGS3), RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), and DICER-LIKE proteins (DCLs). Nonetheless, how these components are coordinated to produce siRNAs is unclear. Here, we show that SGS3 forms condensates via phase separation in vivo and in vitro. SGS3 interacts with RDR6 and drives it to form siRNA bodies in cytoplasm, which is promoted by SGS3-targeted RNAs. Disrupting SGS3 phase separation abrogates siRNA body assembly and siRNA biogenesis, whereas coexpression of SGS3 and RDR6 induces siRNA body formation in tobacco and yeast cells. Dysfunction in translation and mRNA decay increases the number of siRNA bodies, whereas DCL2/4 mutations enhance their size. Purification of SGS3 condensates identifies numerous RNA-binding proteins and siRNA processing components. Together, our findings reveal that SGS3 phase separation-mediated formation of siRNA bodies is essential for siRNA production and gene silencing.

Generalized Muscular Hypermetabolism Caused by Mitochondrial Myopathy Shown on 18 F-FDG PET/CT.

ABSTRACT: An 18-year-old man presented with progressive exercise intolerance and muscle weakness for 1 year with recent acute exacerbation. Laboratory test demonstrated lactic acidosis. 18 F-FDG PET/CT was performed to exclude malignancy and showed generalized muscular hypermetabolism. Muscle biopsy combined with patient's history suggested mitochondrial myopathy. This report illustrates that mitochondrial myopathy may present as generalized muscular hypermetabolism on 18 F-FDG PET/CT and thus should be added to the differential diagnoses.

Neurological disorders associated with glutamic acid decarboxylase 65 antibodies: Clinical spectrum and prognosis of a cohort from China.

Objective: To describe clinical phenotypes and prognosis of neurological autoimmunity related to glutamic acid decarboxylase 65 (GAD65) antibodies in China. Method: In this retrospective observational study from Peking Union Medical College Hospital, we identified patients with neurological disorders related to GAD65 antibodies (cell-based assay) from May 2015 to September 2021. Clinical manifestations, immunotherapy responsiveness, and outcomes were collected after obtaining informed consent from all patients. Results: Fifty-five patients were included: 40 (72.73%) were women and initial neurological symptoms developed at 42(34-55) years of age. The median time to the nadir of the disease was 5 months (range from 1 day to 48 months). The clinical syndromes included limbic encephalitis (LE) or epilepsy (Ep) (n = 34, 61.82%), stiff-person syndromes (SPS) (n = 18, 32.73%), autoimmune cerebellar ataxia (ACA) (n = 11, 20%), and overlap syndrome in eight (14.55%) patients. Thirty-two (58.2%) patients had comorbidities of other autoimmune diseases, including Hashimoto thyroiditis (n = 17, 53.13%), T1DM (n = 11, 34.78%), vitiligo (n = 6, 18.75%), and others (n=5, 15.63%). Two (3.64%) patients had tumors, including thymoma and small cell lung cancer. Fifty-one (92.7%) patients received first-line immunotherapy (glucocorticoids and/or IV immunoglobulin), and 4 (7.3%) received second-line immunotherapy (rituximab). Long-term immunotherapy (mycophenolate mofetil) was administered to 23 (41.8%) patients. At the median time of 15 months (IQR 6-33.75 month, range 3-96 month) of follow-up, the patients' median modified Rankin Score (mRS) had declined from 2 to 1. Thirty-eight (70.4%) patients experienced clinical improvement (mRS declined ≥1), 47 (87%) had favorable clinical outcomes (mRS ≤2), and nine were symptom-free (16.7%). The sustained response to immunotherapy ranged from 7/15 (63.63%) in ACA patients and 22/34 (64.7%) in LE/Ep patients to 14/17 (82.35%) in SPS patients. Conclusions: LE/Ep was the most common neurological phenotype of GAD65 antibody neurological autoimmunity in our cohort. Most patients had comorbidities of other autoimmune diseases, but underlying tumors were rare. Most patients responded to immunotherapy. However, the long-term prognosis varied among different clinical phenotypes.

Concurrent chemoradiotherapy using gemcitabine and nedaplatin in recurrent or locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with recurrent or locally advanced head and neck squamous cell carcinoma (HNSCC) typically have limited treatment options and poor prognosis. AIM: To evaluate the efficacy and safety of two drugs with potent radio-sensitization properties including gemcitabine and nedaplatin as concurrent chemoradiotherapy regimens in treating HNSCC. METHODS: This single-arm prospective study enrolled patients with HNSCC to receive gemcitabine on days 1 and 8 and nedaplatin on days 1 to 3 for 21 days. Intensity-modulated radiation therapy with a conventional fraction was delivered 5 days per week. Objective response rate (ORR), disease control rate, and toxicity were observed as primary endpoints. Overall survival (OS) and progression free survival were recorded and analyzed as secondary endpoints. RESULTS: A total of 24 patients with HNSCC were enrolled. During the median 22.4-mo follow-up, both ORR and disease control rate were 100%. The one-year OS was 75%, and one-year progression-free survival (PFS) was 66.7% (median PFS was 15.1 mo). Recurrent HNSCC patients had a poorer prognosis than the treatment-naïve patients, and patients who achieved complete response had better survival than those in the PR group (all P < 0.05). The most common grade 1-4 (100%) or grade 3-4 toxicities (75%) were hematological, and the most common grade 3-4 non-hematological toxicity was mucositis in 17 (71%) patients. CONCLUSION: Gemcitabine plus nedaplatin with concurrent chemoradiotherapy is a therapeutic option for HNSCC with predictable tolerability. Considering the high adverse event rate, the optimized dose and schedule must be further explored.

Secondary Gastrointestinal Amyloidosis With Increased 18 F-FDG Uptake as the Only Presentation in a Patient With Multiple Myeloma.

ABSTRACT: A 63-year-old woman presented with abdominal pain and hematochezia was referred for 18 F-FDG PET/CT for the underlying malignancy. PET/CT detected diffuse thickening of the bowel walls with intense radioactivity in the colons. She was later diagnosed with multiple myeloma and secondary gastrointestinal amyloidosis, and achieved complete response of myeloma and amyloidosis after 9 cycles of chemotherapy. This case highlighted that gastrointestinal abnormality caused by amyloidosis might be the only presenting symptoms and findings in 18 F-FDG PET/CT in patients with multiple myeloma.

Structure engineering of lanthanide functionalized metal-organic frameworks: A versatile tool for the early diagnosis of pheochromocytomas and paragangliomas.

As a main extracellular metabolite of dopamine, 3-methoxytyramine (3-MT) is considered a potential biomarker of pheochromocytomas and paragangliomas. Therefore, the determination of 3-MT is of great significance in the early diagnosis of disease. However, it remains challenging for detecting 3-MT in consideration of sensitivity and accuracy. Here, a luminescent  Eu3+ functionalized metal-organic frameworks （Eu3+@Al-MOF）with ultra-high chemical stability was constructed based on postsynthetic modification. Such a rational design greatly enhances the fluorescence signal of Eu3+@Al-MOF and it is endowed with excellent properties as a luminescent sensor to detect 3-MT in urine system. Intriguingly, the strong red emitting derived from antenna effect was significantly interdicted upon addition of 3-MT through the interaction between 3-MT and the ligand. The proposed sensing system exhibited many appealing analytical performances, such as excellent selectivity, high sensitivity and quick response. Remarkably, the developed paper-based sensor not only provides a portable and reliable strategy for direct detection of 3-MT but also expands the application of visual analysis tools. This work represents the first effort in designing a luminescent sensor to determine the metabolite biomarker 3-MT level and provides a new method for biomedical analysis.

Near-Infrared Emissive Lanthanide Metal-Organic Frameworks for Targeted Biological Imaging and pH-Controlled Chemotherapy.

Near-infrared window II (NIR-II, 1000-1700 nm) imaging displays the advantages in deep-tissue high-contrast imaging in vivo on the strength of the high temporal-spatial resolution and deeper penetration. However, the clinical utility of NIR-II imaging agents is limited by their single function. Herein, for the first time, we report the design of a multifunctional drug delivery system (DDS) assembly, CQ/Nd-MOF@HA nanohybrids, with NIR-II fluorescence (1067 nm), large Stokes shifts, and ultrahigh quantum yield, which combined targeted NIR-II luminescence bioimaging and pH-controlled drug delivery. The nanoscale metal-organic framework (MOF) as a highly promising multifunctional DDS for targeted NIR-II bioimaging and chemotherapy in vitro and in vivo lays the foundation of the MOF-based DDS for further clinical diagnosis and treatment.

Metal-organic framework-encapsulated nanoparticles for synergetic chemo/chemodynamic therapy with targeted H2O2 self-supply.

Nanocatalytic cancer therapy based on chemodynamic therapy, which converts hydrogen peroxide (H2O2) into toxic reactive oxygen species via the Fenton-like reaction, is regarded as a promising therapeutic strategy due to its specific response toward the tumor microenvironment (TME). However, the H2O2 concentration in TME (100 µM to 1 mM) is insufficient and introducing enough H2O2 or H2O2-generating agents is challenging. In view of this, we report a drug delivery system, CaO2/DOX@Cu/ZIF-8@HA (CDZH), which is capable of targeted H2O2 self-supply and exhibits outstanding chemo/chemodynamic synergetic therapy capability. CaO2/DOX@Cu/ZIF-8@HA is synthesized by fabricating biodegradable Cu/ZIF-8 shell-encapsulated CaO2 nanoparticles, loading chemotherapy drug doxorubicin, and coating a hyaluronic acid shell. In an acidic tumor microenvironment, the CDZH nanostructures targeted the release of doxorubicin, Cu2+, and CaO2. Doxorubicin affects chemotherapy and bioimaging, and CaO2 supplies H2O2 through a Cu-Fenton-like reaction to generate hydroxyl radicals with high oxidation activity for chemodynamic therapy. In brief, the drug delivery system combined targeted H2O2 self-supply and targeted bioimaging possess the potential of an efficient synergistic strategy for chemodynamic therapy and chemotherapy.

Outstanding Drug-Loading/Release Capacity of Hollow Fe-Metal-Organic Framework-Based Microcapsules: A Potential Multifunctional Drug-Delivery Platform.

Owing to their characteristic structures, metal-organic frameworks (MOFs) are considered as the leading candidate for drug-delivery materials. However, controlling the synthesis of MOFs with uniform morphology and high drug-loading/release efficiencies is still challenging, which greatly limits their applications and promotion. Herein, a multifunctional MOF-based drug-delivery system (DDS) with a controlled pore size of 100-200 nm for both therapeutic and bioimaging purposes was successfully synthesized in one step. Fe-MOF-based microcapsules were synthesized through a competitive coordination method, which was profited from the intrinsic coordination characteristics of the Fe element and the host-guest supramolecular interactions between Fe3+ and polyoxometalates anions. This as-synthesized macroporous DDS could greatly increase the drug-loading/release rate (77%; 83%) and serve as a magnetic resonance (MR) contrast agent. Because an Fe-containing macroporous DDS presents ultrahigh drug loading/release, the obtained 5-FU/Fe-MOF-based microcapsules displayed good biocompatibility, extremely powerful inhibition of tumor growth, and satisfactory MR imaging capability. Given all these advantages, this study integrates high therapeutic effect and diagnostic capability via a simple and effective morphology-controlling strategy, aiming at further facilitating the applications of MOFs in multifunctional drug delivery.

Extensive Intraspinal Hypermetabolism Caused by Neurobrucellosis Shown on 18F-FDG PET/CT.

A 55-year-old man and a 52-year-old man presenting with neurological symptoms were referred for F-FDG PET/CT for the underlying malignancy. In both cases, extensive intraspinal hypermetabolism was observed in F-FDG PET/CT. The cerebrospinal fluid culture finally confirmed infection of Brucella. This report illustrates that neurobrucellosis may present as intraspinal hypermetabolism on F-FDG PET/CT, and thus it should be added to the differential diagnosis.

Synergism of cisplatin-oleanolic acid co-loaded hybrid nanoparticles on gastric carcinoma cells for enhanced apoptosis and reversed multidrug resistance.

Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was core-shell structured and well-dispersed nanoparticles with size around 100 nm. The HN/CDDP/OA showed high stability and biocompatibility with pH-responsive drug release. Moreover, the CM modification in HN also demonstrated highly elevated tumor-homing nature than bare CC. Finally, the feasibility of HN/CDDP/OA in the treatment of gastric cancer (MGC-803 cell line) was assessed. HN/CDDP/OA showed better performance than mono systems with enhanced apoptosis and capable of reversing multidrug resistance (MDR) of cancer cells.

Hollow structural metal-organic frameworks exhibit high drug loading capacity, targeted delivery and magnetic resonance/optical multimodal imaging.

Metal-organic frameworks (MOFs) are attractive in designing drug delivery systems for the treatment of cancer because of their unique porous properties. However, the search for multifunctional MOFs with high drug loading and magnetic resonance/fluorescence imaging capacities is still a challenge and they have rarely been reported. In this article, using the intrinsic advantages of MOFs, hollow Fe-MOFs with biomolecular grafting were fabricated and shown to be capable of loading much more drugs and exhibiting targeted drug delivery, pH-controlled drug release and magnetic resonance/fluorescence imaging. Benefiting from their hollow structures, the drug loading capacity is as high as 35%. Due to post-modification with folic acid (FA) and the fluorescent reagent (5-FAM) and the existence of Fe(iii), in vitro experiments indicate that Fe-MOF-5-NH2-FA-5-FAM/5-FU can target cancer cells HepG-2 and display excellent magnetic resonance/fluorescence imaging. Furthermore, in vivo biodistribution indicates that Fe-MOF-5-NH2-FA-5-FAM/5-FU can accumulate in the tumor. Taken together, our work integrates high drug loading and bioimaging into a single MOF successfully and reveals the enormous potential of the functionalized MOF for drug delivery and bioimaging.

A highly selective and sensitive fluorescent sensor based on Tb3+-functionalized MOFs to determine arginine in urine: a potential application for the diagnosis of cystinuria.

A unique metal-organic framework with the formula [Cd4(H2L)2(L)·H2O]·3H2O (H4L = 5,5'-(1H-1,2,4-triazole-3,5-diyl)diisophthalic acid) was successfully constructed under solvothermal conditions. The frameworks with multiple free Lewis base sites and Lewis acid sites exhibited easily sensitized properties. After the encapsulation of Tb3+ cations, the as-synthesized Tb3+@Cd-MOF demonstrated strong luminescence induced by the efficient energy transfer from the bridging ligands to the Tb3+ cations, with the potential to serve as a chemical sensor. Interestingly, Tb3+@Cd-MOF was proven to be a very promising and highly selective and sensitive luminescent platform for the quantitative detection of arginine, which is the biomarker of cystinuria. The fluorescent probe presented high selectivity to arginine in urine with strong luminescence quenching. Furthermore, a convenient fluorescence-based test paper for the visual detection of arginine in applications was prepared. For the first time, arginine was quantified and monitored in urine by a highly efficient recyclable fluorescent sensor based on Tb3+-functionalized MOF hybrids, which may be a potential candidate for the further development of clinical diagnostic tools.