Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Impact of artificial intelligence arrhythmia mapping on time to first ablation, procedure duration, and fluoroscopy use.

INTRODUCTION: Artificial intelligence (AI) ECG arrhythmia mapping provides arrhythmia source localization using 12-lead ECG data; whether this information impacts procedural efficiency is unknown. We performed a retrospective, case-control study to evaluate the hypothesis that AI ECG mapping may reduce time to ablation, procedural duration, and fluoroscopy. MATERIALS AND METHODS: Cases in which system output was used were retrospectively enrolled according to IRB-approved protocols at each site. Matched control cases were enrolled in reverse chronological order beginning on the last day for which the technology was unavailable. Controls were matched based upon physician, institution, arrhythmia, and a predetermined complexity rating. Procedural metrics, fluoroscopy data, and clinical outcomes were assessed from time-stamped medical records. RESULTS: The study group consisted of 28 patients (age 65 ± 11 years, 46% female, left atrial dimension 4.1 ± 0.9 cm, LVEF 50 ± 18%) and was similar to 28 controls. The most common arrhythmia types were atrial fibrillation (n = 10), premature ventricular complexes (n = 8), and ventricular tachycardia (n = 6). Use of the system was associated with a 19.0% reduction in time to ablation (133 ± 48 vs. 165 ± 49 min, p = 0.02), a 22.6% reduction in procedure duration (233 ± 51 vs. 301 ± 83 min, p < 0.001), and a 43.7% reduction in fluoroscopy (18.7 ± 13.3 vs. 33.2 ± 18.0 min, p < 0.001) versus controls. At 6 months follow-up, arrhythmia-free survival was 73.5% in the study group and 63.3% in the control group (p = 0.56). CONCLUSION: Use of forward-solution AI ECG mapping is associated with reductions in time to first ablation, procedure duration, and fluoroscopy without an adverse impact on procedure outcomes or complications.

Prospective exploration of the role of combined internalizing symptoms in self-reported memory among older adults during the COVID-19 pandemic.

OBJECTIVES: A growing literature suggests depression and anxiety increase risk of cognitive decline. However, few studies have examined their combined effects on cognition, among older adults, especially during periods of high stress. METHOD: Based on a sample of community dwelling older adults (N = 576), we evaluated the effects of pre-pandemic anxiety and depressive symptoms, obtained in September 2018, to changes in self-reported memory (SRM) assessed 3 months into the COVID-19 pandemic. RESULTS: In separate models, we found participants with depression scores at least 1-SD above the mean and participants with anxiety scores at least 2-SD above the mean to report a significant decline in SRM. Moderation analyses revealed those with high depressive symptoms (at or above the mean) showed a decrease in SRM regardless of anxiety. The extent to which high pre-pandemic anxiety symptoms influenced SRM is dependent on whether pre-pandemic depression was at or above the mean. CONCLUSIONS: Pre-pandemic depression predicted a decline in SRM regardless of anxiety. Moderation analyses revealed that the extent to which anxiety symptoms influenced SRM was dependent on depression being at or above the mean. Those with high anxiety and depression are at highest risk of experiencing cognitive consequences related to stressful exposures like COVID-19.

eMIFS: A Normalized Hyperbolic Ransomware Deterrence Model Yielding Greater Accuracy and Overall Performance.

Early detection of ransomware attacks is critical for minimizing the potential damage caused by these malicious attacks. Feature selection plays a significant role in the development of an efficient and accurate ransomware early detection model. In this paper, we propose an enhanced Mutual Information Feature Selection (eMIFS) technique that incorporates a normalized hyperbolic function for ransomware early detection models. The normalized hyperbolic function is utilized to address the challenge of perceiving common characteristics among features, particularly when there are insufficient attack patterns contained in the dataset. The Term Frequency-Inverse Document Frequency (TF-IDF) was used to represent the features in numerical form, making it ready for the feature selection and modeling. By integrating the normalized hyperbolic function, we improve the estimation of redundancy coefficients and effectively adapt the MIFS technique for early ransomware detection, i.e., before encryption takes place. Our proposed method, eMIFS, involves evaluating candidate features individually using the hyperbolic tangent function (tanh), which provides a suitable representation of the features' relevance and redundancy. Our approach enhances the performance of existing MIFS techniques by considering the individual characteristics of features rather than relying solely on their collective properties. The experimental evaluation of the eMIFS method demonstrates its efficacy in detecting ransomware attacks at an early stage, providing a more robust and accurate ransomware detection model compared to traditional MIFS techniques. Moreover, our results indicate that the integration of the normalized hyperbolic function significantly improves the feature selection process and ultimately enhances ransomware early detection performance.

Trustworthy High-Performance Multiplayer Games with Trust-but-Verify Protocol Sensor Validation.

Multiplayer online video games are a multibillion-dollar industry, to which widespread cheating presents a significant threat. Game designers compromise on game security to meet demanding performance targets, but reduced security increases the risk of potential malicious exploitation. To mitigate this risk, game developers implement alternative security sensors. The alternative sensors themselves become a liability due to their intrusive and taxing nature. Online multiplayer games with real-time gameplay are known to be difficult to secure due to the cascading exponential nature of many-many relationships among the components involved. Behavior-based security sensor schemes, or referees (a trusted third party), could be a potential solution but require frameworks to obtain the game state information they need. We describe our Trust-Verify Game Protocol (TVGP), which is a sensor protocol intended for low-trust environments and designed to provide game state information to help support behavior-based cheat-sensing detection schemes. We argue TVGP is an effective solution for applying an independent trusted referee capability to trust-lacking subdomains and demands high-performance requirements. Our experimental results validate high efficiency and performance standards for TVGP. We identify and discuss the operational domain assumptions of the TVGP validation testing presented here.

Axillary Lymph Node Dissection is Associated with Improved Survival Among Men with Invasive Breast Cancer and Sentinel Node Metastasis.

BACKGROUND: Male breast cancer (MBC) is rare, and management is extrapolated from trials that enroll only women. It is unclear whether contemporary axillary management based on data from landmark trials in women may also apply to men with breast cancer. This study aimed to compare survival in men with positive sentinel lymph nodes after sentinel lymph node biopsy (SLNB) alone versus complete axillary dissection (ALND). PATIENTS AND METHODS: Using the National Cancer Database, men with clinically node-negative, T1 and T2 breast cancer and 1-2 positive sentinel nodes who underwent SLNB or ALND were identified from 2010 to 2020. Both 1:1 propensity score matching and multivariate regression were used to identify patient and disease variables associated with ALND versus SLNB. Survival between ALND and SLNB were compared using Kaplan-Meier methods. RESULTS: A total of 1203 patients were identified: 61.1% underwent SLNB alone and 38.9% underwent ALND. Treatment in academic centers (36.1 vs. 27.7%; p < 0.0001), 2 positive lymph nodes on SLNB (32.9 vs. 17.3%, p < 0.0001) and receipt or recommendation of chemotherapy (66.5 vs. 52.2%, p < 0.0001) were associated with higher likelihood of ALND. After propensity score matching, ALND was associated with superior survival compared with SLNB (5-year overall survival of 83.8 vs. 76.0%; log-rank p = 0.0104). DISCUSSION: The results of this study suggest that among patients with early-stage MBC with limited sentinel lymph node metastasis, ALND is associated with superior survival compared with SLNB alone. These findings indicate that it may be inappropriate to extrapolate the results of the ACOSOG Z0011 and EORTC AMAROS trials to MBC.

Temporal Data Correlation Providing Enhanced Dynamic Crypto-Ransomware Pre-Encryption Boundary Delineation.

Ransomware is a type of malware that employs encryption to target user files, rendering them inaccessible without a decryption key. To combat ransomware, researchers have developed early detection models that seek to identify threats before encryption takes place, often by monitoring the initial calls to cryptographic APIs. However, because encryption is a standard computational activity involved in processes, such as packing, unpacking, and polymorphism, the presence of cryptographic APIs does not necessarily indicate an imminent ransomware attack. Hence, relying solely on cryptographic APIs is insufficient for accurately determining a ransomware pre-encryption boundary. To this end, this paper is devoted to addressing this issue by proposing a Temporal Data Correlation method that associates cryptographic APIs with the I/O Request Packets (IRPs) based on the timestamp for pre-encryption boundary delineation. The process extracts the various features from the pre-encryption dataset for use in early detection model training. Several machine and deep learning classifiers are used to evaluate the accuracy of the proposed solution. Preliminary results show that this newly proposed approach can achieve higher detection accuracy compared to those reported elsewhere.

18F-FSPG PET/CT Imaging of System xC- Transporter Activity in Patients with Primary and Metastatic Brain Tumors.

Background The PET tracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) targets the system xC- cotransporter, which is overexpressed in various tumors. Purpose To assess the role of 18F-FSPG PET/CT in intracranial malignancies. Materials and Methods Twenty-six patients (mean age, 54 years ± 12; 17 men; 48 total lesions) with primary brain tumors (n = 17) or brain metastases (n = 9) were enrolled in this prospective, single-center study (ClinicalTrials.gov identifier: NCT02370563) between November 2014 and March 2016. A 30-minute dynamic brain 18F-FSPG PET/CT scan and a static whole-body (WB) 18F-FSPG PET/CT scan at 60-75 minutes were acquired. Moreover, all participants underwent MRI, and four participants underwent fluorine 18 (18F) fluorodeoxyglucose (FDG) PET imaging. PET parameters and their relative changes were obtained for all lesions. Kinetic modeling was used to estimate the 18F-FSPG tumor rate constants using the dynamic and dynamic plus WB PET data. Imaging parameters were correlated to lesion outcomes, as determined with follow-up MRI and/or pathologic examination. The Mann-Whitney U test or Student t test was used for group mean comparisons. Receiver operating characteristic curve analysis was used for performance comparison of different decision measures. Results 18F-FSPG PET/CT helped identify all 48 brain lesions. The mean tumor-to-background ratio (TBR) on the whole-brain PET images at the WB time point was 26.6 ± 24.9 (range: 2.6-150.3). When 18F-FDG PET was performed, 18F-FSPG permitted visualization of non-18F-FDG-avid lesions or allowed better lesion differentiation from surrounding tissues. In participants with primary brain tumors, the predictive accuracy of the relative changes in influx rate constant Ki and maximum standardized uptake value to discriminate between poor and good lesion outcomes were 89% and 81%, respectively. There were significant differences in the 18F-FSPG uptake curves of lesions with good versus poor outcomes in the primary brain tumor group (P < .05) but not in the brain metastases group. Conclusion PET/CT imaging with (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (18F-FSPG) helped detect primary brain tumors and brain metastases with a high tumor-to-background ratio. Relative changes in 18F-FSPG uptake with multi-time-point PET appear to be helpful in predicting lesion outcomes. Clinical trial registration no. NCT02370563 © RSNA, 2022 Online supplemental material is available for this article.

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Association of heart failure with procedural complications and in-hospital outcomes from left atrial appendage occlusion device implantation in patients with atrial fibrillation: insights from the national inpatient sample of 62 980 procedures.

AIMS: To determine outcomes in atrial fibrillation (AF) patients undergoing percutaneous left atrial appendage occlusion (LAAO) with concomitant heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Data were extracted from National Inpatient Sample for calendar years 2015-2019. LAAO device implantations were identified on the basis of ICD-10-CM code of 02L73DK. The outcomes assessed in our study included complications, in-patient mortality, and resource utilization. A total of 62 980 LAAO device implantations were studied. HFpEF (14.4%, n = 9040) and HFrEF (11.2%, n = 7100) were associated with a higher prevalence of major complications and in-patient mortality in crude analysis. In the multivariate model adjusted for potential confounders, HFpEF and HFrEF were not associated with major complications [adjusted odds ratio (aOR) 1.04, 95% confidence interval (CI) 0.93-1.16 and aOR 1.07, 95% CI 0.95-1.21] or in-patient mortality (aOR 1.48, 95% CI 0.85-2.55 and aOR 1.26, 95% CI 0.67-2.38). HFpEF and HFrEF were associated with prolonged length of stay (LOS) > 1 day (aOR 1.41, 95% CI 1.31-1.53 and aOR 1.66, 95% CI 1.53-1.80) and increased hospitalization costs > median cost 24 752$ (aOR 1.26, 95% CI 1.19-1.34 and aOR 1.21, 95% CI 1.13-1.29). CONCLUSION: The prevalence of HF in AF patients undergoing percutaneous LAAO was approximately 26%. HF was not independently associated with major complications and in-patient mortality but was associated with prolonged LOS and higher hospitalization costs.

Brief, interoceptive exposure focused treatment for anxiety in mild cognitive impairment.

Anxiety is common in older adults with mild cognitive impairment (MCI), and Alzheimer's disease and related dementias (ADRD). Anxiety has also been identified as a risk factor for cognitive decline. Brief interventions targeting risk mechanisms of anxiety, such as anxiety sensitivity (AS), have been effective in reducing overall anxiety in a variety of populations. This case series investigated the feasibility and efficacy of a brief AS intervention in anxious older adults with MCI (n = 9). Paired samples t-test results indicate that this intervention is capable of significantly reducing AS as measured by the Anxiety Sensitivity Index-3 (Δ = 5.11, Hedges g = 0.82, P < 0.05). Given these large AS reductions and high acceptability, further investigation of this intervention is warranted in older adults with MCI.

A Survey of Crypto Ransomware Attack Detection Methodologies: An Evolving Outlook.

Recently, ransomware attacks have been among the major threats that target a wide range of Internet and mobile users throughout the world, especially critical cyber physical systems. Due to its unique characteristics, ransomware has attracted the attention of security professionals and researchers toward achieving safer and higher assurance systems that can effectively detect and prevent such attacks. The state-of-the-art crypto ransomware early detection models rely on specific data acquired during the runtime of an attack's lifecycle. However, the evasive mechanisms that these attacks employ to avoid detection often nullify the solutions that are currently in place. More effort is needed to keep up with an attacks' momentum to take the current security defenses to the next level. This survey is devoted to exploring and analyzing the state-of-the-art in ransomware attack detection toward facilitating the research community that endeavors to disrupt this very critical and escalating ransomware problem. The focus is on crypto ransomware as the most prevalent, destructive, and challenging variation. The approaches and open issues pertaining to ransomware detection modeling are reviewed to establish recommendations for future research directions and scope.

Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19.

Coronaviruses represent a diverse family of enveloped positive-sense single stranded RNA viruses. COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus-2, is a highly contagious respiratory disease transmissible mainly via close contact and respiratory droplets which can result in severe, life-threatening respiratory pathologies. It is understood that glutathione, a naturally occurring antioxidant known for its role in immune response and cellular detoxification, is the target of various proinflammatory cytokines and transcription factors resulting in the infection, replication, and production of reactive oxygen species. This leads to more severe symptoms of COVID-19 and increased susceptibility to other illnesses such as tuberculosis. The emergence of vaccines against COVID-19, usage of monoclonal antibodies as treatments for infection, and implementation of pharmaceutical drugs have been effective methods for preventing and treating symptoms. However, with the mutating nature of the virus, other treatment modalities have been in research. With its role in antiviral defense and immune response, glutathione has been heavily explored in regard to COVID-19. Glutathione has demonstrated protective effects on inflammation and downregulation of reactive oxygen species, thereby resulting in less severe symptoms of COVID-19 infection and warranting the discussion of glutathione as a treatment mechanism.

CRKL promotes hepatocarcinoma through enhancing glucose metabolism of cancer cells via activating PI3K/Akt.

Abnormal glucose metabolism may contribute to cancer progression. As a member of the CRK (v-crk sarcoma virus CT10 oncogene homologue) adapter protein family, CRKL (CRK-like) associated with the development and progression of various tumours. However, the exact role and underlying mechanism of CRKL on energy metabolism remain unknown. In this study, we investigated the effect of CRKL on glucose metabolism of hepatocarcinoma cells. CRKL and PI3K were found to be overexpressed in both hepatocarcinoma cells and tissues; meanwhile, CRKL up-regulation was positively correlated with PI3K up-regulation. Functional investigations revealed that CRKL overexpression promoted glucose uptake, lactate production and glycogen synthesis of hepatocarcinoma cells by up-regulating glucose transporters 1 (GLUT1), hexokinase II (HKII) expression and down-regulating glycogen synthase kinase 3ß (GSK3ß) expression. Mechanistically, CRKL promoted glucose metabolism of hepatocarcinoma cells via enhancing the CRKL-PI3K/Akt-GLUT1/HKII-glucose uptake, CRKL-PI3K/Akt-HKII-glucose-lactate production and CRKL-PI3K/Akt-Gsk3ß-glycogen synthesis. We demonstrate CRKL facilitates HCC malignancy via enhancing glucose uptake, lactate production and glycogen synthesis through PI3K/Akt pathway. It provides interesting fundamental clues to CRKL-related carcinogenesis through glucose metabolism and offers novel therapeutic strategies for hepatocarcinoma.

Undertreatment of Gallbladder Cancer: A Nationwide Analysis.

BACKGROUND: Gallbladder cancer has a high mortality rate and an increasing incidence. The current National Comprehensive Cancer Network (NCCN) guidelines recommend resection for all T1b and higher-stage cancers. This study aimed to evaluate re-resection rates and the associated survival impact for patients with gallbladder cancer. METHODS: Patients with gallbladder adenocarcinoma who underwent resection were identified from the National Cancer Database (2004-2015). Re-resection was defined as definitive surgery within 180 days after the first operation. Propensity scores were created for the odds of a patient having a re-resection. Patients were matched 1:2. Survival analyses were performed using the Kaplan-Meier and Cox proportional hazard methods. RESULTS: The study identified 6175 patients, and 466 of these patients (7.6%) underwent re-resection. Re-resection was associated with younger median age (65 vs 72 years; p < 0.0001), private insurance (41.6% vs 27.1%; p < 0.0001), academic centers (50.4% vs 29.7%; p < 0.0001), and treatment location in the Northeast (22.8% vs 20.4%; p = 0.0011). Compared with no re-resection, re-resection was associated with pT stage (pT2: 47.6% vs 42.8%; p = 0.0139) and pN stage (pN1-2: 28.1% vs 20.7%; p < 0.0001), negative margins on final pathology (90.1% vs 72.6%; p < 0.0001), and receipt of chemotherapy (53.7% vs 35.8%; p < 0.0001). The patients who underwent re-resection demonstrated significantly longer overall survival (OS) than the patients who did not undergo re-resection (median OS, 44.0 vs 23.0 months; p < 0.0001). After propensity score-matching, re-resection remained associated with superior survival (median OS, 44.0 vs 31.0 months; p = 0.0004). CONCLUSIONS: Re-resection for gallbladder cancer is associated with improved survival but remains underused, particularly for early-stage disease.

Contemporary procedural trends of Watchman percutaneous left atrial appendage occlusion in the United States.

OBJECTIVE: To determine trends in real-world utilization and in-hospital adverse events from Watchman implantation since its approval by the Food and Drug Administration in 2015. BACKGROUND: The risk of embolic stroke caused by atrial fibrillation is reduced by oral anticoagulants, but not all patients can tolerate long-term anticoagulation. Left atrial appendage occlusion with the Watchman device has emerged as an alternative therapy. METHODS: This was a retrospective cohort study utilizing data from National Inpatient Sample for calendar years 2015-2017. The outcomes assessed in this study were associated complications, in-hospital mortality, and resource utilization trends after Watchman implantation. Trends analysis were performed using analysis of variance. Multivariable adjusted logistic regression analysis was performed to determine predictors of mortality. RESULTS: A total of 17 700 patients underwent Watchman implantation during the study period. There was a significantly increased trend in the number of Watchman procedures performed over the study years (from 1195 in 2015 to 11 165 devices in 2017, p < .01). A significant decline in the rate of complications (from 26.4% in 2015% to 7.9% in 2017, p < .01) and inpatient mortality (from 1.3% in 2015% to 0.1% in 2017, p < .01) were noted. Predictors of in-hospital mortality included a higher CHA2 DS2 -VASc score (odds ratio [OR]: 2.61 per 1-point increase, 95% confidence interval [CI]: 1.91-3.57), chronic blood loss anemia (OR: 3.63, 95% CI: 1.37-9.61) and coagulopathy (OR: 4.90, 95% CI: 2.32-10.35). CONCLUSION: In contemporary United States clinical practice, Watchman utilization has increased significantly since approval in 2015, while complications and in-patient mortality have declined.

[18F]-C-SNAT4: an improved caspase-3-sensitive nanoaggregation PET tracer for imaging of tumor responses to chemo- and immunotherapies.

Positron emission tomography (PET) imaging of apoptosis can noninvasively detect cell death in vivo and assist in monitoring tumor response to treatment in patients. While extensive efforts have been devoted to addressing this important need, no apoptosis PET imaging agents have yet been approved for clinical use. This study reports an improved 18F-labeled caspase-sensitive nanoaggregation tracer ([18F]-C-SNAT4) for PET imaging of tumor response to chemo- and immunotherapies in preclinical mouse models. METHODS: We rationally designed and synthesized a new PET tracer [18F]-C-SNAT4 to detect cell death both in vitro and in vivo. In vitro radiotracer uptake studies were performed on drug-sensitive and -resistant NSCLC cell lines (NCI-H460 and NCI-H1299, respectively) treated with cisplatin at different doses. In vivo therapy response monitoring by [18F]-C-SNAT4 PET imaging was evaluated with two treatment modalities-chemotherapy and immunotherapy in two tumor xenografts in mice. Radiotracer uptake in the tumors was validated ex vivo using γ-counting and cleaved caspase-3 immunofluorescence. RESULTS: This [18F]-C-SNAT4 PET tracer was facilely synthesized and displayed improved serum stability profiles. [18F]-C-SNAT4 cellular update was elevated in NCI-H460 cells in a time- and dose-dependent manner, which correlated well with cell death. A significant increase in [18F]-C-SNAT4 uptake was measured in NCI-H460 tumor xenografts in mice. In contrast, a rapid clearance of [18F]-C-SNAT4 was observed in drug-resistant NCI-H1299 in vitro and in tumor xenografts. Moreover, in BALB/C mice bearing murine colon cancer CT26 tumor xenografts receiving checkpoint inhibitors, [18F]-C-SNAT4 showed its ability for monitoring immunotherapy-induced apoptosis and reporting treatment-responding mice from non-responding. CONCLUSION: The uptake of [18F]-C-SNAT4 in tumors received chemotherapy and immunotherapy is positively correlated with the tumor apoptotic level and the treatment efficacy. [18F]-C-SNAT4 PET imaging can monitor tumor response to two different treatment modalities and predict the therapeutic efficacy in preclinical mouse models.

Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.

PURPOSE: In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). METHODS: Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aß+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. RESULTS: SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aß+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. CONCLUSION: Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain.

Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC50: 2.7 nM). Subsequent radiosynthesis of [11C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [11C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [11C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [11C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.

The potential role of miR-124-3p in tumorigenesis and other related diseases.

MicroRNAs (miRNAs) are a class of single-stranded noncoding and endogenous RNA molecules with a length of 18-25 nucleotides. Previous work has shown that miR-124-3p leads to malignant progression of cancer including cell apoptosis, migration, invasion, drug resistance, and also recovers neural function, affects adipogenic differentiation, facilitates wound healing through control of various target genes. miR-124-3p has been mainly previously characterized as a tumor suppressor regulating tumorigenesis and progression in several cancers, such as hepatocellular carcinoma (HCC), gastric cancer (GC), bladder cancer, ovarian cancer (OC), and leukemia, as a tumor promotor in breast cancer (BC), and it has been also widely studied in a variety of neurological diseases, like Parkinson's disease (PD), dementia and Alzheimer's disease (AD), and cardiovascular diseases, ulcerative colitis (UC), acute respiratory distress syndrome (ARDS). To lay the groundwork for future therapeutic strategies, in this review we mainly focus on the most recent years of literature on the functions of miR-124-3p in related major cancers, as well as its downstream target genes. Although current work as yet provides an incomplete picture, miR-124-3p is still worthy of more attention as a practical and effective clinical biomarker.