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.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). METHODS: Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. RESULTS: Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. CONCLUSION: [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. TRIAL REGISTRATION: 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05603559 .

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.

Surgical resection of primary tumors improves survival in patients with lung metastases: a population-based SEER analysis.

Background: The lung is a common site for cancer metastasis. Some cancer patients would develop lung metastases throughout the course of their illness. However, choosing surgical resection of the primary tumor (SRPT) or palliative treatment in patients with lung metastases remains controversial. Methods: Lung metastatic patients diagnosed from 2010 to 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Selected patients were divided into two subgroups (surgery and non-surgery). Further, all the 58 tumor types were classified into 13 subtypes. The clinical and demographic features were examined by the Fisher's exact test, chi-squared test, or z-test. Overall survival (OS) was analyzed using the Kaplan-Meier (K-M) estimator and a log-rank test for each primary tumor type. Multivariable survival analyses of OS were performed using the Cox proportional hazards model. Results: Among the 118,088 patients selected for study, 18,688 (15.83%) patients had undergone surgery. The analyses demonstrated that there was a significant association between SRPT and better OS in patients with lung metastases. The median survival time increased from 4.0 months in the non-surgery group to 19.0 months in the surgery group. Multivariate Cox regression analyses further validated that patients who underwent SRPT had an improved OS. Conclusions: The current study demonstrated that patients with lung metastases can benefit from SRPT. SRPT should be considered in patients with lung metastases. Properly designed prospective randomized clinical trials would be required to further verify the conclusion.

Feasibility of 18F-florzolotau quantification in patients with Alzheimer's disease based on an MRI-free tau PET template.

OBJECTIVES: Quantification of tau accumulation using positron emission tomography (PET) is critical for the diagnosis of Alzheimer's disease (AD). This study aimed to evaluate the feasibility of 18F-florzolotau quantification in patients with AD using a magnetic resonance imaging (MRI)-free tau PET template, since individual high-resolution MRI is costly and not always available in practice. METHODS: 18F-florzolotau PET and MRI scans were obtained in a discovery cohort including (1) patients within the AD continuum (n = 87), (2) cognitively impaired patients with non-AD (n = 32), and (3) cognitively unimpaired subjects (n = 26). The validation cohort comprised 24 patients with AD. Following MRI-dependent spatial normalization (standard approach) in randomly selected subjects (n = 40) to cover the entire spectrum of cognitive function, selected PET images were averaged to create the 18F-florzolotau-specific template. Standardized uptake value ratios (SUVRs) were calculated in five predefined regions of interest (ROIs). MRI-free and MRI-dependent methods were compared in terms of continuous and dichotomous agreement, diagnostic performances, and associations with specific cognitive domains. RESULTS: MRI-free SUVRs had a high continuous and dichotomous agreement with MRI-dependent measures for all ROIs (intraclass correlation coefficient ≥ 0.980; agreement ≥ 94.5%). Similar findings were observed for AD-related effect sizes, diagnostic performances with respect to categorization across the cognitive spectrum, and associations with cognitive domains. The robustness of the MRI-free approach was confirmed in the validation cohort. CONCLUSIONS: The use of an 18F-florzolotau-specific template is a valid alternative to MRI-dependent spatial normalization, improving the clinical generalizability of this second-generation tau tracer. KEY POINTS: • Regional 18F-florzolotau SUVRs reflecting tau accumulation in the living brains are reliable biomarkers for the diagnosis, differential diagnosis, and assessment of disease severity in patients with AD. • The 18F-florzolotau-specific template is a valid alternative to MRI-dependent spatial normalization, improving the clinical generalizability of this second-generation tau tracer.

Genome-based risk assessment for foodborne Salmonella enterica from food animals in China: A One Health perspective.

Salmonella is one of the most common causes of foodborne bacterial disease. Animal-borne foods are considered the primary sources of Salmonella transmission to humans. However, genomic assessment of antimicrobial resistance (AMR) and virulence of Salmonella based on One Health approach remains obscure in China. For this reason, we analyzed the whole genome sequencing data of 134 Salmonella isolates recovered from different animal and meat samples in China. The 134 Salmonella were isolated from 2819 samples (4.75 %) representing various sources (pig, chicken, duck, goose, and meat) from five Chinese provinces (Zhejiang, Guangdong, Jiangxi, Hunan, and Qinghai). AMR was evaluated by the broth dilution method using 13 different antimicrobial agents, and results showed that 85.82 % (115/134) of isolates were resistant to three or more antimicrobial classes and were considered multidrug-resistant (MDR). Twelve sequence types (STs) were detected, with a dominance of ST469 (29.85 %, 40/134). The prediction of virulence genes showed the detection of cdtB gene encoding typhoid toxins in one isolate of S. Muenster recovered from chicken, while virulence genes associated with type III secretion systems were detected in all isolates. Furthermore, plasmid-type prediction showed the abundance of IncFII(S) (13/134; 9.7 %) and IncFIB(S) (12/134; 8.95 %) in the studied isolates. Together, this study demonstrated the ability to use whole-genome sequencing (WGS) as a cost-effective method to provide comprehensive knowledge about foodborne Salmonella isolates in One Health surveillance approach.

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.

Cumulative evidence for associations between genetic variants in interleukin 17 family gene and risk of human diseases.

Background: Genetic association studies have elucidated the link of variants in the interleukin 17 (IL-17) family genes with susceptibility to human diseases, yet have obtained controversial outcomes. Therefore, we sought to update comprehensive synopsis of variants in the IL-17 family genes with susceptibility to human diseases. Methods: Our study screened the Pubmed and Web of Science to enroll eligible articles and performed a meta-analysis, then graded the cumulative evidence of significant association using Venice criteria and false-positive report probability test, and finally assessed the function of variants with strong evidence. Results: Seven variants in IL-17 family genes had significant relationships with susceptibility to 18 human diseases identified by meta-analyses. Strong evidence was assigned to 4 variants (IL-17A rs2275913, IL-17A rs8193037, IL-17F rs1889570, IL-17F rs763780) with susceptibility to 6 human diseases (lung and cervical cancer, spondyloarthritis, asthma, multiple sclerosis, rheumatoid arthritis), moderate to 2 variants with risk of 5 diseases, weak to 5 variants with risk of 10 diseases. Bioinformatics analysis suggested that the variants with strong evidence might fall in putative functional regions. Additionally, positive relationships for 5 variants with risk of 4 diseases (based on two datasets) and 14 variants with risk of 21 diseases (based on one dataset) were considered noteworthy. Conclusions: This study offers updated and comprehensive clues that variants in the IL-17 family genes are significantly linked with susceptibility to cervical, lung cancer, asthma, multiple sclerosis, rheumatoid arthritis and spondyloarthritis, and elucidates the crucial role of the IL-17 regions in the genetic predisposition to cancer or noncancerous diseases.

Epidemiological evidence for associations between variants in CHRNA genes and risk of lung cancer and chronic obstructive pulmonary disease.

Background: Genetic studies have previously reported that single-nucleotide polymorphisms (SNPs) in CHRNA genes (such as CHRNA3, CHRNA4, CHRNA5, or CHRNA3-CHRNA5-CHRNB4 clusters) are linked to the risk of neoplastic and non-neoplastic diseases. However, these conclusions were controversial and no systematic research synopsis has been available. We aimed to synthesize current knowledge of variants in the CHRNA genes on the risk of diseases. Methods: We systematically searched for publications using PubMed, Medline, and Web of Science on or before 25 August 2021. A total of 1,818 publications were identified, of which 29 were deemed eligible for inclusion that could be used to perform meta-analysis based on at least three data sources to assess whether the morbidity associated with neoplastic and non-neoplastic diseases can be attributed to SNPs in CHRNA genes. To further evaluate the authenticity of cumulative evidence proving significant associations, the present study covered the Venice criteria and false-positive report probability tests. Through the Encyclopedia of DNA Elements (ENCODE) project, we created functional annotations for strong associations. Results: Meta-analyses were done for nine genetic variants with two diseases {chronic obstructive pulmonary disease (COPD) and lung cancer (LC)}that had at least three data sources. Interestingly, eight polymorphisms were significantly related to changes in the susceptibility COPD and LC (p < 0.05). Of these, strong evidence was assigned to six variants (28 significant associations): CHRNA3 rs1051730, CHRNA3 rs6495309, and CHRNA5 rs16969968 with COPD risk, and CHRNA3 rs1051730, CHRNA3 rs578776, CHRNA3 rs6495309, CHRNA3 rs938682, CHRNA5 rs16969968, and CHRNA5 rs588765 with LC risk; moderate evidence was assigned to five SNPs (12 total associations) with LC or COPD risk. Data from ENCODE and other public databases showed that SNPs with strong evidence may be located in presumptive functional regions. Conclusions: Our study summarized comprehensive evidence showing that common mutations in CHRNA genes are strongly related to LC and COPD risk. The study also elucidated the vital function of CHRNA genes in genetic predispositions to human diseases.

Pan-cancer analysis of the prevalence and associated factors of lung metastasis and the construction of the lung metastatic classification system.

This study first presents an analysis of the prevalence and associated factors of the lung metastasis (LM) database and then uses this analysis to construct an LM classification system. Using cancer patient data gathered from the surveillance, epidemiology, and end results (SEER) database, this study shows that the prevalence of LM is not consistent among different cancers; that is, the prevalence of LM ranges from 0.0013 [brain; 95% confidence interval (95% CI); 0.0010-0.0018] to 0.234 ("other digestive organs"; 95% CI; 0.221-0.249). This study finds that advanced age, poor grade, higher tumor or node stage, and metastases including bone, brain, and liver are positively related to LM occurrence, while female gender, income, marital status, and insured status are negatively related. Then, this study generates four categories from 58 cancer types based on prevalence and influence factors and satisfactorily validates these. This classification system reflects the LM risk of different cancers. It can guide individualized treatment and the management of these synchronous metastatic cancer patients and help clinicians better distribute medical resources.

Paving the way for precise diagnostics of antimicrobial resistant bacteria.

The antimicrobial resistance (AMR) crisis from bacterial pathogens is frequently emerging and rapidly disseminated during the sustained antimicrobial exposure in human-dominated communities, posing a compelling threat as one of the biggest challenges in humans. The frequent incidences of some common but untreatable infections unfold the public health catastrophe that antimicrobial-resistant pathogens have outpaced the available countermeasures, now explicitly amplified during the COVID-19 pandemic. Nowadays, biotechnology and machine learning advancements help create more fundamental knowledge of distinct spatiotemporal dynamics in AMR bacterial adaptation and evolutionary processes. Integrated with reliable diagnostic tools and powerful analytic approaches, a collaborative and systematic surveillance platform with high accuracy and predictability should be established and implemented, which is not just for an effective controlling strategy on AMR but also for protecting the longevity of valuable antimicrobials currently and in the future.

The Association between Dietary Vitamin C Intake and the Risk of Esophageal Cancer: An Updated Dose-Response Meta-Analysis.

Although some epidemiological studies have reported the associations between vitamin C and risk of esophageal cancer, these results are inconsistent. Therefore, we performed an updated meta-analysis to explore the associations between dietary vitamin C intake and risk of esophageal cancer. We used PubMed, Embase, and the Web of Science to screen all published articles, which yielded 18 papers eligible for data extraction (involving 4,126 cases and 36,902 controls), and then pooled the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using random-effects model. As we detected the associations in highest category and the lowest type of dietary vitamin C intake, we discovered that dietary vitamin C intake was negatively correlated to the risk of esophageal cancer. The analysis of subgroup showed a significant counter proportion between vitamin C and the risk of ESCC and EAC. Moreover, the dose-analysis indicated that if increasing dietary intake of vitamin C of 50 mg/day, esophageal cancer risk dropped down 10% (OR = 0.81, 95%CI: 0.75-0.87). In summary, our study provides a comprehensive and updated epidemiological evidence to elucidate the relationships between dietary vitamin C and reduction of esophageal cancer risk. Nevertheless, we still need larger case-control and cohort studies to confirm these connections.

Complementary Utility of Dopamine Transporter and Tau PET Imaging in the Diagnosis of Progressive Supranuclear Palsy: A Case Report.

ABSTRACT: A 50-year-old woman developed gait disturbances, tendency to fall backwards, bradykinesia, and memory loss over the previous 6 months. Brain 18F-FDG PET/CT was unable to distinguish among APSs (atypical parkinsonian syndromes); PET investigations of dopamine transporter (DAT) function (11C-CFT) and tau pathology (18F-APN-1607) were performed. 11C-CFT PET revealed severe loss of striatal DAT function, whereas significant tau accumulation was observed in the brainstem, basal ganglia, and globus pallidus on 18F-APN-1607 PET. Such finding suggested diagnosis of PSP (progressive supranuclear palsy). This case highlights the value of DAT and tau PET imaging in diagnosis of PSP and differential diagnosis ofAPSs.

Characterization of the interaction between carbon black and three important antioxidant proteins using multi spectroscopy and modeling simulations.

A major user of carbon black is the pigment and dyes industry, where carbon black is incorporated into paints, inks, printers, and plastics. However, little is known about the mechanism underlying the toxicity of carbon black to antioxidant proteins. Carbon black can cause oxidative stress to organisms after they invade into the body. Antioxidant proteins play a key role in keeping the organism from nanoparticle-induced oxidative damage and tend to bind with nanoparticles immediately after their invading into the biological environment, so it is meaningful to elucidate the toxicity of nanoparticles on the antioxidant proteins. In this study, the toxicity of carbon black (SB100) on three different antioxidant proteins (TF (transferrin), SOD (superoxide dismutase), and LYZ (lysozyme)) were investigated. The multi-spectra studies indicated that SB100 interacted with these three proteins and changed their structure in different ways. SB100 changed the microenvironment of fluorophores in SOD and LYZ by quenching the fluorescence spectra of the two enzymes, while changed that of TF by increasing the fluorescence intensity of TF. SB100 changed the secondary structure of these three proteins by decreasing the α-helix content of TF and increasing that of SOD and LYZ. Moreover, SB100 changed the hydrophobicity of the three proteins in different ways as well. And SOD exhibits a more severe activity inhibition than LYZ after exposed to SB100. In summary, SB100 caused different structural and functional changes to these three antioxidant enzymes.

Carbon black induced DNA damage and conformational changes to mouse hepatocytes and DNA molecule: A combined study using comet assay and multi-spectra methods.

Carbon black (CB), a carbonaceous nanoparticle, has been widely applied in our daily lives and used as a typical model to study environmental safety and health impacts of airborne particles. Although the potential negative effects of CB to organisms have been reported a lot, very limited work is focused on the genotoxicity of CB on molecular and cellular level simultaneously. Herein, we investigated the interaction mechanism between CB and DNA molecule in depth by multiple spectra measurement, UV-vis absorption and ionic strength measurement. The fluorescence spectroscopy, ironic strength measurement and UV absorption indicated that CB changed the structure of DNA and interacted with DNA in an electrostatic binding mode. CD (circular dichroism) spectra proved no significant effects were caused by CB on the base stacking and helicity bands of DNA, which further verified that electrostatic binding is the main binding mode between CB and DNA. On the cellular level, the comet assay shows that CB exposure could cause a remarkable DNA strand break to the mouse hepatocytes after 24 co-incubation. This combined investigation suggests that CB could cause a serious genotoxicity both on molecular and cellular level.