Diagnostic value of quantitative myocardial blood flow assessment by NaI(Tl) SPECT in detecting significant stenosis: a prospective, multi-center study.

OBJECTIVES: The aim of this prospective multi-center study was to investigate the diagnostic value of myocardial blood flow (MBF) quantification using NaI(Tl)-based single-photon emission computed tomography (SPECT) for determining coronary artery disease (CAD) defined by quantitative coronary angiography (QCA). BACKGROUND: Absolute quantitation of MBF and myocardial flow reserve (MFR) using SPECT is clinically feasible; however, whether flow quantification using NaI(Tl) SPECT is superior to commonly performed SPECT myocardial perfusion imaging (MPI) in determining CAD has not been evaluated. METHODS: Patients with suspected or known CAD underwent pharmacological stress/rest dynamic SPECT imaging and routine SPECT MPI followed by QCA. Obstructive disease was defined as ≥ 50% reduction in luminal diameter on QCA. RESULTS: One hundred fifty-four patients (462 vessels) were included in the analysis. Obstructive CAD was detected in 76/154 patients (49.4%) and 112/462 vessels (24.2%). Optimal cut-off values were 1.86 mL/min/g for stress MBF and 1.95 for MFR, respectively. Stress MBF and MFR were more sensitive than MPI in both individual patients (stress MBF vs MPI: 81.6% vs 51.3%; MFR vs MPI: 72.4% vs 51.3%) and in coronary vascular regions (stress MBF vs MPI: 78.6% vs 31.3%; MFR vs MPI: 75.9% vs 31.3%; all P < .01). In receiver operating characteristic curve analysis, quantification revealed a significantly greater area under the curve than MPI at the patient (stress MBF vs MPI: 0.761 vs 0.641; MFR vs MPI: 0.770 vs 0.641) and the vessel (stress MBF vs MPI: 0.745 vs 0.613; MFR vs MPI: 0.756 vs 0.613; all P < .05) levels. Integrating quantitative SPECT measures with MPI significantly increased the area under the curve and improved the discriminatory and reclassification capacity. CONCLUSION: Flow quantification using NaI(Tl) SPECT provides superior sensitivity and discriminatory capacity to MPI in detecting significant stenosis. Clinical trial registration NCT03637725.

Characterizing the hyper- and hypometabolism in temporal lobe epilepsy using multivariate machine learning.

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy, presenting both structural and metabolic abnormalities in the ipsilateral mesial temporal lobe. While it has been demonstrated that the metabolic abnormalities in MTLE actually extend beyond the epileptogenic zone, how such multidimensional information is associated with the diagnosis of MTLE remains to be tested. Here, we explore the whole-brain metabolic patterns in 23 patients with MTLE and 24 healthy controls using [18 F]fluorodeoxyglucose PET imaging. Based on a multivariate machine learning approach, we demonstrate that the brain metabolic patterns can discriminate patients with MTLE from controls with a superior accuracy (>95%). Importantly, voxels showing the most extreme contributing weights to the classification (i.e., the most important regional predictors) distribute across both hemispheres, involving both ipsilateral negative weights over the anterior part of lateral and medial temporal lobe, posterior insula, and lateral orbital frontal gyrus, and contralateral positive weights over the anterior frontal lobe, temporal lobe, and lingual gyrus. Through region-of-interest analyses, we verify that in patients with MTLE, the negatively weighted regions are hypometabolic, and the positively weighted regions are hypermetabolic, compared to controls. Interestingly, despite that both hypo- and hypermetabolism have mutually contributed to our model, they may reflect different pathological and/or compensative responses. For instance, patients with earlier age at epilepsy onset present greater hypometabolism in the ipsilateral inferior temporal gyrus, while we find no evidence of such association with hypermetabolism. In summary, quantitative models utilizing multidimensional brain metabolic information may provide additional assistance to presurgical workups in TLE.

Poly(A)-DG: A deep-learning-based domain generalization method to identify cross-species Poly(A) signal without prior knowledge from target species.

In eukaryotes, polyadenylation (poly(A)) is an essential process during mRNA maturation. Identifying the cis-determinants of poly(A) signal (PAS) on the DNA sequence is the key to understand the mechanism of translation regulation and mRNA metabolism. Although machine learning methods were widely used in computationally identifying PAS, the need for tremendous amounts of annotation data hinder applications of existing methods in species without experimental data on PAS. Therefore, cross-species PAS identification, which enables the possibility to predict PAS from untrained species, naturally becomes a promising direction. In our works, we propose a novel deep learning method named Poly(A)-DG for cross-species PAS identification. Poly(A)-DG consists of a Convolution Neural Network-Multilayer Perceptron (CNN-MLP) network and a domain generalization technique. It learns PAS patterns from the training species and identifies PAS in target species without re-training. To test our method, we use four species and build cross-species training sets with two of them and evaluate the performance of the remaining ones. Moreover, we test our method against insufficient data and imbalanced data issues and demonstrate that Poly(A)-DG not only outperforms state-of-the-art methods but also maintains relatively high accuracy when it comes to a smaller or imbalanced training set.

lncRNA NEAT1 prompts autophagy and apoptosis in MPTP-induced Parkinson's disease by impairing miR-374c-5p.

Long non-coding RNAs (lncRNAs) play biological roles in brain disorder and neurodegenerative diseases. As the functions of lncRNA NEAT1 in Parkinson's disease (PD) remain unknown, in the present study, we aimed to explore the roles and underlying molecular mechanisms of NEAT1 in PD. A PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and a cell model of SH-SY5Y induced by N-methyl-4-phenylpyridinium (MPP+) were established. The ratio of tyrosine hydroxylase (TH+) cells was determined by immunofluorescence assay, and the behavioral changes in mice were observed using pole tests and rotarod tests. The cellular viability and apoptosis of SH-SY5Y were detected by MTT assay and flow cytometric analysis, respectively, and the number of autophagosomes was subsequently measured by transmission electron microscopy. High-performance liquid chromatography was performed to detect the content of dopamine, and a dual-luciferase reporter assay was used to clarify the target of NEAT1 simultaneously. The results demonstrated that the level of NEAT1 was upregulated in the MPTP-induced PD mice, dopamine neurons, and the SH-SY5Y cells treated with MPP+, whereas the level of miR-374c-5p was downregulated. NEAT1 level was positively correlated with MPP+ in a concentration-dependent manner. NEAT1 inhibition efficiently facilitated cell proliferation but inhibited apoptosis and autophagy in the MPP+-treated SH-SY5Y cells. Additionally, silencing of NEAT1 increased the TH+ rate of neurons and suppressed autophagy greatly in PD mice. As a possible target of NEAT1, miR-374c-5p could impact on the apoptosis and autophagy of the SH-SY5Y cells. NEAT1 inhibition upregulated the expression of miR-374c-5p, enhanced SH-SY5Y cell viability, and repressed autophagy and apoptosis in MPTP-induced PD mice. These findings indicated a potential therapeutic role of NEAT1 in treating PD.

Regional cerebral blood flow correlates eating abnormalities in frontotemporal dementia.

BACKGROUND: Eating abnormalities are one of the core symptoms of frontotemporal dementia (FTD), especially for behavioral variant FTD (bvFTD), and semantic variant primary progressive aphasia (svPPA). METHODS: A group of FTD patients (43 bvFTD, 29 svPPA) underwent single-photon emission CT (SPECT) to measure the region cerebral blood flow (rCBF). The Cambridge Behavioral Inventory (CBI) was used to measure the eating abnormalities. A whole-brain voxel-based correlation between eating abnormalities and rCBF was investigated. RESULTS: In bvFTD, the sweet preference was correlated with decreased rCBF in the bilateral gyrus rectus and temporal pole, and eating the same food was correlated with the left ventral anterior cingulate cortex. In svPPA, decreased rCBF in the left inferior temporal gyrus was correlated with eating the same food. CONCLUSIONS: These findings showed that either different symptoms in the same subtype or the same symptom in different subtypes of FTD may be correlated with different regions, indicating different neural mechanisms behind them.

Monocytes, microglia, and CD200-CD200R1 signaling are essential in the transmission of inflammation from the periphery to the central nervous system.

Peripheral inflammation is known to trigger neuroinflammation and neurodegenerative disease. However, the key components during the propagation of inflammation from the periphery to the central nervous system (CNS) remain unclear. Lipopolysaccharide (LPS) was administered to Sprague-Dawley rats to induce peripheral inflammation. An intravenous injection and an intranigral injection of clodronate liposomes were given to deplete monocytes and microglia, respectively. Recombinant CD200 fusion protein (CD200Fc) or an anti-CD200R1 antibody was injected into the substantia nigra to manipulate the involvement of CD200 and CD200R1. Immunohistochemistry and immunofluorescence staining were used to measure microglial activation and dopaminergic neuronal loss. The expression of brain pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1ß) and CD200-CD200R1 signaling were measured by quantitative RT-PCR. Our data showed that the peripheral LPS injection activated the microglia and induced an increase in the levels of pro-inflammatory cytokines (i.e., tumor necrosis factor alpha, IL-1ß). The depletion of either monocytes or microglia suppressed these inflammatory effects that were induced by peripheral LPS administration. The peripheral LPS injection increased the expression of CD200 and CD200R1 in the substantia nigra. Dopaminergic neuronal loss induced by the peripheral LPS injection was accelerated by the blockade of CD200-CD200R1 signaling with an anti-CD200R1 antibody and attenuated by intensifying the signaling with CD200Fc. These results highlight the importance of monocytes, microglia, and CD200-CD200R1 signaling in the transmission of inflammation from the periphery to the CNS.

Impact of boronate capping groups on biological characteristics of novel (99m)Tc(III) complexes [(99m)TcCl(CDO)(CDOH)2B-R] (CDOH2 = cyclohexanedione dioxime).

This study sought to explore the impact of boronate groups on the heart uptake and myocardial retention of novel (99m)Tc(III) complexes [(99m)TcCl(CDO)(CDOH)2B-R] ((99m)Tc-ISboroxime: R = isoxazol-4-yl (IS); (99m)Tc-MPboroxime: R = N-methylpyridinium (MP); (99m)Tc-PAboroxime: R = pyrazol-3-yl (PA); (99m)Tc-PYboroxime: R = pyridin-3-yl (PY); and (99m)Tc-5Uboroxime: R = uracil-5-yl (5U)). All five new (99m)Tc(III) radiotracers were prepared in high yield and high radiochemical purity (RCP = 90-98%), and they remained stable in the kit mixture for >6 h. Biodistribution and imaging (planar and SPECT) studies were carried out using Sprague-Dawley (SD) rats. Planar image quantification was performed to compare their myocardial retention and liver clearance kinetics. It was found that their heart retention and liver clearance curves were best fitted to the biexponential decay function. The initial heart uptake at 0-1 min after injection followed the general ranking order of (99m)Tc-ISboroxime (4.98 ± 1.05%ID) ∼ (99m)Tc-Teboroxime (4.56 ± 0.91%ID) ∼ (99m)Tc-PAboroxime (4.03 ± 1.23%ID) ∼ (99m)Tc-PYboroxime (4.07 ± 0.80%ID) > (99m)Tc-5Uboroxime (3.24 ± 0.67%ID) > (99m)Tc-MPboroxime (2.53 ± 0.65%ID). The fast-phase myocardial retention time followed the general order of (99m)Tc-PAboroxime (3.21 ± 0.29 min) > (99m)Tc-Teboroxime (1.63 ± 0.40 min) ∼ (99m)Tc-PYboroxime (1.57 ± 0.29 min) ∼ (99m)Tc-ISboroxime (1.55 ± 0.32 min) > (99m)Tc-MPboroxime (0.68 ± 0.16 min) > (99m)Tc-5Uboroxime (0.33 ± 0.11 min). (99m)Tc-PAboroxime (3.05 ± 1.10%ID/g) and (99m)Tc-ISboroxime (3.75 ± 0.68%ID/g) had the 2 min initial heart uptake very close to that of (99m)Tc-Teboroxime (3.30 ± 0.50%ID/g). However, the myocardial retention time of (99m)Tc-PAboroxime was significantly longer than that of (99m)Tc-ISboroxime and (99m)Tc-Teboroxime. Even though the best time window is 0-5 min for SPECT image acquisition, high quality SPECT images could be obtained during the first 30 min postinjection of (99m)Tc-PAboroxime in SD rats. This statement was supported by the SPECT/CT studies in normal pigs. On the basis of results from this study, it was concluded that boronate groups had significant impact on the heart uptake, myocardial retention, and liver clearance kinetics of (99m)Tc(III) complexes [(99m)TcCl(CDO)(CDOH)2B-R]. The combination of high initial heart uptake with longer myocardial retention makes it possible to image the heart with (99m)Tc-PAboroxime during the first 30 min using both standard and specialized cardiac SPECT cameras.

FITC-conjugated cyclic RGD peptides as fluorescent probes for staining integrin αvß3/αvß5 in tumor tissues.

This study sought to evaluate FITC-conjugated cyclic RGD peptides (FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2) as fluorescent probes for in vitro assays of integrin αvß3/αvß5 expression in tumor tissues. FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2 were prepared, and their integrin αvß3/αvß5 binding affinity was determined using the displacement assay against (125)I-echistatin bound to U87MG glioma cells. IC50 values of FITC-Galacto-RGD2, FITC-3P-RGD2, and FITC-RGD2 were calculated to be 28 ± 8, 32 ± 7, and 89 ± 17 nM, respectively. The integrin αvß3/αvß5 binding affinity followed a general trend: FITC-Galacto-RGD2 ∼ FITC-3P-RGD2 > FITC-RGD2. The xenografted tumor-bearing models were established by subcutaneous injection of 5 × 10(6) tumor cells into shoulder flank (U87MG, A549, HT29, and PC-3) or mammary fat pad (MDA-MB-435) of each athymic nude mouse. Three to six weeks after inoculation, the tumor size was 0.1-0.3 g. Tumors were harvested for integrin αvß3/αvß5 staining, as well as hematoxylin and eosin (H&E) staining. Six human carcinoma tissues (colon cancer, pancreatic cancer, lung adenocarcinoma, squamous cell lung cancer, gastric cancer, and esophageal cancer) were obtained from recently diagnosed cancer patients. Human carcinoma slides were deparaffinized in xylene, rehydrated with ethanol, and then used for integrin αvß3/αvß5 staining, as well as H&E staining. It was found that the tumor staining procedures with FITC-conjugated cyclic RGD peptides were much simpler than those with the fluorescence-labeled integrin αvß3 antibodies. Since FITC-RGD2, FITC-3P-RGD2, and FITC-Galacto-RGD2 were able to co-localize with the fluorescence-labeled integrin ß3 antibody, their tumor localization and tumor cell binding are integrin αvß3-specific. Quantification of the fluorescent intensity in five xenografted tumors (U87MG, MDA-MB-435, A549, HT29, and PC-3) and six human carcinoma tissues revealed an excellent linear relationship between the relative integrin αvß3/αvß5 expression levels determined with FITC-Galacto-RGD2 and those obtained with the fluorescence-labeled anti-human integrin ß3 antibody. There was also an excellent linear relationship between the tumor uptake (%ID/g) of (99m)Tc-3P-RGD2 (an integrin αvß3/αvß5-targeted radiotracer) and the relative integrin αvß3/αvß5 expression levels from the quantification of fluorescent intensity in the tumor tissues stained with FITC-Galacto-RGD2. These results suggest that FITC-conjugated cyclic RGD peptides might be useful to correlate the in vitro findings with the in vivo imaging data from an integrin αvß3/αvß5-targeted radiotracer. The results from this study clearly showed that the FITC-conjugated cyclic RGD peptides (particularly FITC-3P-RGD2 and FITC-Galacto-RGD2) are useful fluorescent probes for assaying relative integrin αvß3/αvß5 expression levels in tumor tissues.

Development of kit formulations for (99m) TcN-MPO: a cationic radiotracer for myocardial perfusion imaging.

The objective of this study was to develop a kit formulation for [(99m) TcN(mpo)(PNP5)](+) (MPO = 2-mercaptopyridine oxide), ((99m) TcN-MPO) to support its clinical evaluations as a SPECT radiotracer. Radiolabeling studies were performed using three different formulations (two-vial formulation and single-vial formulations with/without SnCl2 ) to explore the factors influencing radiochemical purity (RCP) of (99m) TcN-MPO. We found that the most important factor affecting the RCP of (99m) TcN-MPO was the purity of PNP5. (99m) TcN-MPO was prepared >98% RCP (n = 20) using the two-vial formulation. For single-vial formulations with/without SnCl2 , ß-cyclodextrin (ß-CD) is particularly useful as a stabilizer for PNP5. The RCP of (99m) TcN-MPO was 95-98% using ß-CD, but its RCP was only 90-93% with γ-cyclodextrin (γ-CD). It seems that PNP5 fits better into the inner cavity of ß-CD, which forms more stable inclusion complex than γ-CD in the single-vial formulations. The results from biodistribution and imaging studies in Sprague-Dawley rats clearly demonstrated biological equivalence of three different formulations. Single photon-emission computed tomography data suggested that high quality images could be obtained at 0-30-min post-injection without significant interference from the liver radioactivity. Considering the ease for (99m) Tc-labeling and high RCP of (99m) TcN-MPO, the non-SnCl2 single-vial formulation is an attractive choice for future clinical studies.

Comparing biofilm reactors inoculated with Shewanella for decolorization of Reactive Black 5 using different carrier materials.

This study assessed the performance of biofilm reactors inoculated with azo dye degrading Shewanella for the decolorization of Reactive Black 5 (RB5), using three different carrier materials, namely almond shell biochar, moving bed biofilm reactor (MBBR), and polypropylene carrier (PPC). The reactors were fed with low-nutrient artificial wastewater containing RB5, and all three carriers showed good RB5 decolorization performance, with varying efficiencies. Liquid Chromatography-Mass Spectrometry analysis revealed distinct RB5 degradation pathways associated with each carrier, influenced by carrier materials and microbial communities. The MBBR carrier exhibited good stability due to its rough surface and microbial aggregates. Sequencing results highlighted differences in the microbial community structures among the carriers. Shewanella predominated the functional bacteria in the MBBR and PPC carriers, while the biochar carrier fostered highly efficient degrading microbial communities. The physicochemical properties of carrier materials significantly influenced the microbial community and RB5 degradation efficiency. These findings provide valuable insights for optimizing biofilm reactors for dye-containing wastewater treatment.

Effect of body mass index and cholesterol-rich apolipoprotein-B-containing lipoproteins on clinical outcome in NSCLC patients treated with immune checkpoint inhibitors-based therapy: A retrospective analysis.

OBJECTIVES: Obesity and hypercholesterolemia are linked to unfavor clinical outcomes. Recent studies declared the paradox that high body mass index (BMI) and serum cholesterol were independently connected to better clinical outcome of immune checkpoint inhibitors (ICIs) monotherapy in non-small cell lung cancer (NSCLC). The aim of the study is to investigate the prognosis of BMI and serum cholesterol in ICIs-based therapy. METHODS: This is a retrospective study of 95 NSCLC patients treated with ICIs-based therapy at the Department of Oncology and Lung Cancer Center of China-Japan Friendship Hospital. Treatment efficacy was assessed using durable clinical benefit (DCB) versus nondurable benefit (NDB), best response (active vs. nonactive), and progression-free survival (PFS). The prognostic value of BMI, LDL-C, and RC was determined by multivariate regression analyses, while controlling for confounding factors including age, gender, diabetes status, smoking history, and statin usage. BMI was considered a confounding factor in the analysis when examining the impact of lipoproteins. RESULTS: In our study, we found that in the whole group, BMI ≥25 kg/m2 was linked to a higher risk of poor therapeutic response (OR = 5.92, 95% CI 1.99-19.51, p.val = 0.002) and shorter progression-free survival (HR = 3.00, 95% CI 1.59-5.68, p.val = 0.001). In addition, low levels of RC were associated with better therapeutic response (OR = 0.12, 95% CI 0.02-0.64, p.val = 0.019), while low levels of serum LDL-C were found to predict longer PFS (HR = 0.40, 95% CI 0.19-0.82, p.val = 0.012). These associations were consistent in advanced NSCLC patients receiving ICIs and chemotherapy. CONCLUSIONS: Our study suggest that BMI ≥25 kg/m2 and elevated levels of apoB-containing lipoproteins, including LDL-C and RC, could potentially serve as useful prognostic markers for predicting poor treatment outcomes in advanced NSCLC patients treated with the combination of chemotherapy and ICIs.

Safety and efficacy of restarting immune checkpoint inhibitors in non-small cell lung cancer patients following immune-related adverse events: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aims to evaluate the safety and efficacy of restarting immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) after experiencing immune-related adverse events (irAEs). METHODS: A comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted to identify studies investigating the safety and efficacy of restarting ICIs in NSCLC patients after irAEs. Outcome measures, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) after ICI restarting, were extracted. Meta-analysis was performed using the R meta-package. RESULTS: Four studies involving a total of 326 subjects were included, comprising 137 patients who restarted ICI treatment after irAEs and 189 patients who did not restart ICI treatment. The results revealed that ICI restarting was associated with an increased ORR (OR = 2.36, 95% CI 1.49-3.84), prolonged PFS (HR = 0.60, 95% CI 0.42-0.86), and prolonged OS (HR = 0.65, 95% CI 0.43-0.99) compared to non-restarting. The incidence of irAEs after ICI restarting was 45% (95% CI 0.27-0.63). CONCLUSION: Restarting ICI treatment after discontinuation due to previous irAEs appears to be a reasonable option for NSCLC patients. However, a comprehensive assessment of the potential benefits and risks to individual patients is crucial, and close monitoring of irAEs is warranted.

[A comparison of ventilation/perfusion single photon emission CT and CT pulmonary angiography for diagnosis of pulmonary embolism].

OBJECTIVE: To assess the diagnostic accuracy of ventilation/perfusion (V/Q) single photon emission CT (SPECT) as compared to computed tomographic pulmonary angiography (CTPA) for pulmonary embolism (PE). METHODS: In this prospective multicenter study, 111 patients in whom acute or sub-acute PE was clinically confirmed or suspected were enrolled. The patients underwent one-day method V/Q lung scan (including SPECT and planar imaging) within 3 days before and after completion of CTPA. The European Association of Nuclear Medicine (EANM) guidelines for ventilation/perfusion scintigraphy (2009) reference was used as the evaluation criteria of V/Q SPECT imaging. The refined modified prospective investigation of pulmonary embolism diagnosis (RM-PIOPED) criteria was used for evaluation of planar imaging. According to the direct and indirect signs of PE, the imaging of CTPA was evaluated. All patients were followed for at least 6 months. A diagnosis was finally made by consensus of respiratory physicians, radiologists and nuclear medicine physicians based on the clinical data, laboratory tests, imaging features and follow-up results. The difference among diagnostic methods was evaluated for significance using chi-square test. The receiver operator characteristic (ROC) curve was drawn according to the results of the 3 diagnostic tests. The area under ROC curve (AUC) was calculated and compared. P < 0.05 was considered statistically significant. RESULTS: Among the 111 patients, PE was confirmed in 80, and excluded in 31. The diagnostic sensitivity/specificity/accuracy of V/Q SPECT, planar imaging, and CTPA were 85.9%/93.5%/88.1%, 75.7%/92.9%/81.4%, and 85.5%/90.0%/86.8%, respectively. By ROC curve analysis, the AUC values of V/Q SPECT, planar imaging and CTPA were 0.898, 0.838, and 0.877, respectively; with 95% confidence intervals [CI] 0.831 to 0.966, 0.759 to 0.917, and 0.801 to 0.954, respectively. The area of the fitted smooth ROC curve was statistically significant (P < 0.05) as compared with the area under the reference line. CONCLUSION: The results indicate that SPECT V/Q imaging is superior to V/Q planar scan and CTPA in the diagnosis of PE.

Treatment-related adverse events of immune checkpoint inhibitors combined with angiogenesis inhibitors in advanced lung cancer: A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) with angiogenesis inhibitors have been used to treat advanced lung cancer. Their associated treatment-related adverse events (trAEs) are currently considered acceptable; however, no conclusion has been reached. We aimed to summarize the trAEs caused by ICIs combined with angiogenesis inhibitors in patients with advanced lung cancer. METHODS: Pulled studies met the following criteria: patients with advanced lung cancer who received treatment involving ICIs combined with angiogenesis inhibitors (with or without chemotherapy) in interventional or observational studies. Results included the type and number of trAEs or immune-related adverse events (irAEs), treatment-associated discontinuation and mortality, overall survival (OS), and progression-free survival (PFS). PROSPERO: CRD42022337656. RESULTS: The study enrolled 32 trials involving 2313 patients who had 7768 any-grade trAEs and 1078 grade ≥3 trAEs. The pooled incidences were 87.33% (95% confidence interval [CI]: 79.49-93.65; I2 = 94.04%) for any-grade trAEs, and 38.63% (95% CI: 28.28-49.50; I2 = 95.61%) for grade ≥3 trAEs. There were 132 kinds of any-grade trAEs involving 18 systems, and 99 kinds of grade ≥3 trAEs involving 16 systems. For all trAEs, we observed significant differences in the line of therapy, trial design, therapy combination, and types of angiogenesis inhibitors (all P < 0.05). The rate of trAEs increased with dosage and frequency of medication. Pooled incidences of discontinuation and mortality were 10.64% and 0.81%, respectively. Nearly 647 patients experienced irAEs, including 636 any-grade irAEs and 154 grade ≥3 irAEs. CONCLUSIONS: Overall, the incidence of trAEs caused by ICIs combined with angiogenesis inhibitors is generally acceptable. These trAEs have a wide spectrum nearly covering the full range of adverse events. Grade ≥3 trAEs are more closely associated with angiogenesis inhibitors than any grade. However, treatment-associated mortality remains concerning.

Treatment patterns and clinical outcomes in 157 patients with extensive-stage small cell lung cancer: real-world evidence from a single-center retrospective study.

Background: Immune checkpoint inhibitors (ICIs) have changed the therapeutic options for extensive-stage small-cell lung cancer (ES-SCLC). In this real-world study, we analyzed the treatment patterns in patients with ES-SCLC and evaluated the efficacy of chemotherapy combined with immunotherapy as first-line therapy. Methods: A retrospective analysis was performed on patients with ES-SCLC who received treatment at China-Japan Friendship Hospital (Beijing, China) between August 1, 2020, and April 30, 2023. The treatment patterns appeared in the form of Sunburst Chart and Sankey diagram. The survival analyses were conducted by Kaplan-Meier curves. Results: A total of 157 patients with ES-SCLC were retrospectively included. According to first-line therapy, patients were divided into the chemotherapy (CT) group (n=82) and chemo-immunotherapy (CIT) group (n=75). The median treatment lines were 2[1, 2] and cycles were 8[5, 12], respectively. 82 patients received the second line of therapy, followed by 37 for the third, 15 for the fourth, 11 for the fifth, and 5 for the sixth. Overall, the treatment patterns involved 11 options including 12 chemotherapy regimens, 11 ICIs, and 4 targeted agents. The second-line treatment pattern had the most options (9) and regimens (43). In the first 3 lines, chemotherapy was the largest proportion of treatment options. The addition of ICIs prolonged progression-free survival from 6.77 (95% confidence interval [CI], 6.00-7.87) to 7.33 (95% CI, 6.03-9.80) months (hazard ratio [HR]=0.67, 95% CI, 0.47-0.95; P=0.025), overall survival from 12.97 (10.90-23.3) to 14.33 (12.67-NA) months without statistically significant difference (HR=0.86, 95% CI, 0.55-1.34; P=0.505). Conclusion: The treatment options of patients with ES-SCLC are more diversified. Combination therapy is the current trend, where chemotherapy is the cornerstone. Meanwhile, ICIs participate in almost all lines of treatment. However, the clinical efficacy remains barely satisfactory. We are urgently expecting more breakthrough therapies except immunology will be applied in the clinic.

Efficacy and Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis B or C: A Systematic Review and Meta-Analysis.

Background: Immune checkpoint inhibitors (ICIs) have changed the situation of tumor therapy in recent years. However, for security reasons, those special populations are often excluded from clinical trials, such as infected hepatitis B or hepatitis C patients. ICIs are systematically reviewed and meta-analyzed for the first time in patients infected with hepatitis B or C in this paper. Methods: The relevant studies were searched in PubMed, EMBASE, Cochrane Library, and Web of Science until October 2022. Trials and observational studies meeting the inclusion criteria were included. The outcomes included the effectiveness of ICIs in patients with HBC/HCV (ORR, DCR, mOS, and mPFS), the incidence of adverse reactions, high-grade adverse reactions, and abnormal liver enzymes. At the same time, these indexes were compared with those of uninfected patients. Results: A total of 2,625 patients were enrolled, involving 1,179 patients with hepatitis (HBV or HCV). We found that ICIs showed higher ORR (25.80% vs. 18.10%) and DCR (66.22% vs. 58.74%) in patients with hepatitis B/C than those without infection. In terms of survival time, patients with hepatitis virus infection showed longer mOS (15.44 m vs. 13.30 m) but shorter mPFS (4.94 m vs. 5.01 m) than uninfected patients. As for safety data, patients with hepatitis showed a lower incidence of all-grade irAEs (68.02% vs. 70.43%) than uninfected patients, while that of 3-4 irAEs (21.27% vs. 21.79%) was similar in the two groups. However, hepatic dysfunction was more common and serious in hepatitis patients. Four HBVr and no HCVr were observed. Conclusion: According to this meta-analysis, ICIs are effective and safe for patients with hepatitis B or C, but basic liver enzymes have to be evaluated before treatment to avoid liver adverse events.

Unagi: Deep Generative Model for Deciphering Cellular Dynamics and In-Silico Drug Discovery in Complex Diseases.

Human diseases are characterized by intricate cellular dynamics. Single-cell sequencing provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in-silico drug interventions. Here, we introduce UNAGI, a deep generative neural network tailored to analyze time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modeling and discovery. When applied to a dataset from patients with Idiopathic Pulmonary Fibrosis (IPF), UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation via proteomics reveals the accuracy of UNAGI's cellular dynamics analyses, and the use of the Fibrotic Cocktail treated human Precision-cut Lung Slices confirms UNAGI's predictions that Nifedipine, an antihypertensive drug, may have antifibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including a COVID dataset, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond IPF, amplifying its utility in the quest for therapeutic solutions across diverse pathological landscapes.

lncRNA NEAT1 promotes autophagy of neurons in mice by impairing miR-107-5p.

This work focused on the exploration of NEAT1 in Parkinson's disease (PD) and aimed to explore its effects on PD and related molecular mechanisms. Two experimental models were initially constructed, including MPTP-induced mice in vivo and the MPP+-induced SH-SY5Y cell line in vitro. Immunofluorescence assays were conducted to determine the TH+ positive cell rate. Pole tests and rotarod tests were also performed for the visualization of behavioral changes in mice. Cellular apoptosis was determined using MTT and flow cytometry assays. Changes in the number of autophagosomes were obtained under a transmission electron microscope. The content of dopamine was confirmed by high performance liquid chromatography. The targeted interrelationship between miR-107-5p and NEAT1 was clarified via dual-luciferase reporter gene assays. Meanwhile, mRNA and protein expressions were also detected using qRT-PCR and Western blot respectively. Furthermore, the level of NEAT1 was positively correlated with MPP+ concentration. Interfering with NEAT1 in the present study promoted cellular proliferation and mediated SH-SY5Y cell apoptosis and autophagy treated with MPP+. An increase was discovered in TH positive neurons and suppressive autophagy in PD mice. miR-107-5p was then considered as a NEAT1 putative target involving apoptosis and autophagy of SH-SY5Y cells. Interfering with NEAT1 efficiently facilitated the viability of SH-SY5Y cells and drastically suppressed autophagy and apoptosis of PD mice induced by MPTP- via elevating miR-107-5p level, which indicated that lncRNA NEAT1 acted as a latent therapeutic factor for PD treatment.

SPECT findings on neuropsychiatric symptoms caused by nitrous oxide abuse.

Objective: The aim of the study was to investigate the clinical, neuropsychological, and regional cerebral blood flow (rCBF) perfusion changes in patients with neuropsychiatric symptoms caused by nitrous oxide (N2O) abuse. Methods: A total of 16 patients with neuropsychiatric symptoms caused by nitrous oxide abuse were recruited for this study. The study was carried out in the withdrawal phase of N2O abuse. A 925-1110 MBq 99mTc-ECD was administered intravenously. SPECT/CT images were collected with a low-energy and high-resolution collimator. The region uptake statistics of different brain regions of interest between patients with N2O abuse and normal people of the databases for younger subjects from the Scenium DB Comparison software were calculated automatically. Results: The clinical manifestations of the 16 patients with neuropsychiatric symptoms were mood lability, anxiety, hallucination, delusion, agitation, confusion, and other psychiatric symptoms. In addition, 15 of the patients also complained of memory decline; 14 patients manifested numbness or paresthesia; 14 patients developed limb weakness, and their motor impairments were more severe in the lower limbs than in the upper limbs; and eight patients had urinary and defecation disturbances. In the neuropsychological examination, the BPRS score was 54.69 ± 11.48, the HAMD score was 30.00 ± 11.06, the HAMA score was 18.06 ± 5.77, the MMSE score was 28.06 ± 2.29, and the MoCA score was 25.06 ± 3.40. SPECT showed hypoperfusion in the frontal and temporal lobes, which is consistent with the clinical findings. Conclusion: This was the first study to demonstrate the obvious effect of N2O abuse on CBF in patients with neuropsychiatric symptoms. CBF perfusion imaging is helpful to detect the changes in the local brain functional activity in patients with N2O abuse.