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Purpose. A meta-analysis of randomized controlled trials was performed to compare the efficacy, quality of life (QOL), symptom improvement and toxicities of gefitinib with docetaxel in previously treated advanced non-small-cell lung cancer. Methods. The PubMed database, the Cochrane Library and references of published trials were searched. Two reviewers independently assessed the quality of the trials and extracted data. The hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), relative risks (RRs) for overall response rate, QOL and symptom improvement, and odds ratios (ORs) for main toxicities were pooled using STATA package. Results. Four multicenter, randomized controlled trials involving 2257 patients with previously treated advanced NSCLC were ultimately analyzed. The pooled HRs showed no significant difference in OS and PFS between the two groups (HR == 1.02, 95% CI == 0.92--1.12, p == 0.70; HR == 0.97, 95% CI == 0.88--1.07, p == 0.57, respectively). Gefitinib significantly improved overall response rate (RR == 1.58, 95% CI == 1.02--2.45, p == 0.04) and QOL (RR == 1.55, 95% CI == 1.27--1.88, p == 0.00 by Functional Assessment of Cancer Therapy-Lung and RR == 1.86, 95% CI == 1.43--2.42, p == 0.00 by Trial Outcome Index, respectively). Gefitinib had fewer grade 3 or 4 neutropenia and fatigue (OR == 0.02, 95% CI == 0.01--0.03, p == 0.00; and OR == 0.47, 95% CI == 0.32--0.70, p == 0.00, respectively), but more grade 3 or 4 rash (OR == 2.87, 95% CI == 1.24--6.63, p == 0.01) than docetaxel. The grade 3 or 4 nausea, vomiting and diarrhea and symptom improvement were comparable between the two drugs. Conclusions. In conclusion, although similar OS and PFS, gefitinib showed an advantage over docetaxel in terms of objective response rate, QOL and tolerability. Therefore, gefitinib is an important and valid treatment option for previously treated advanced non-small-cell lung cancer patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to ascertain the relationship between the phosphorylation of FOXO1 and the apoptosis and the proliferation of lymphoma cells so as to further clarify the cellular biology and pathogenesis of the disease. The lymphoma cells Namalwa and Jurkat were treated with PI3K inhibitor wortmannin or etoposide alone or wortmannin plus etoposide with different schedule. The inhibition rates of lymphoma cell growth were examined by XTT assay. Apoptosis were detected by flow cytometry. The expression of p-Akt, p-FOXO1, FOXO1, bim were determined by western blot analysis. Wortmannin induced apoptosis of Jurkat cells and Namalwa cells and inhibited their survival effectively. The rate of growth inhibition and apoptosis of lymphoma cells induced by wortmannin plus etoposide were higher than those induced by etoposide alone. After treated with wortmannin, phosphorylation of FOXO1 remarkably reduced and bim increased. The dephosphorylation of FOXO1 inhibited proliferation of Jurkat cells and Namalwa cells, promoted their apoptosis and sensitized Non-Hodgkin lymphoma cells to etoposide. Bim activated by FOXO1 promoted cells apoptosis. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to investigate the potential involvement of pyruvate kinase M2 (PKM2), an enzyme acting as a rate-limiting enzyme in the final phase of glycolysis, in the regulation of glial activation and brain damage of intracerebral hemorrhage (ICH). Methods: Western blotting and immunofluorescence were performed to investigate PKM2 expression, terminal deoxynucleotidyl transferase deoxyurinary triphosphate (dUTP) nick end labeling staining, hematoxylin and eosin staining, and behavioral tests were employed to evaluate the brain damage of ICH mice, and RNA-seq and bioinformatic analyses were performed to detect gene expression changes in ICH mice treated with TEPP-46. Results: Increased PKM2 levels in perihematomal brain tissue were found starting from 3 days following ICH and peaked at 5 and 7 days post ICH. The increased expression of PKM2 was mainly co-localized with glial fibrillary acidic protein (GFAP)+ astrocytes and ionized calcium binding adaptor molecule-1 (IBA-1)+ microglia. Furthermore, we observed a notable increase in the nuclear translocation of PKM2 in glial cells following ICH. TEPP-46 treatment significantly reduced PKM2 nuclear translocation, and effectively attenuated glial activation and brain injury, and improved functional recovery of mice with ICH. RNA-seq data indicated that 91.1% (205/225) of differentially expressed genes (DEGs) were down-regulated in the TEPP-46 treated groups compared with the vehicle-treated groups in ICH brains. Furthermore, bioinformatic analyses revealed that these down-regulated DEGs were involved in a variety of biological processes, including autophagy and metabolic processes. In addition, the majority of these downregulated DEGs had a primary high expression in neurons, with subsequent expression seen in endothelial cells, microglia, and astrocytes. Conclusions: These results indicate that increased PKM2 nuclear translocation promotes the activation of glial cells after ICH, hence aggravating ICH-induced brain damage, and aggravates the brain injury induced by ICH. This highlights a potential therapeutic target for inhibiting glial activation to attenuate brain injury after ICH. [ABSTRACT FROM AUTHOR]

Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LM PFS) and overall survival (OS) after the diagnosis of LM (OS LM) were analyzed. The median OS LM was 16.0 months and the 3-year OS rate was 22.5%. The PFS LM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P = 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P = 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive. [ABSTRACT FROM AUTHOR]

It is unclear how Toll-like receptor (TLR) 4 signaling affects protein succinylation in the brain after intracerebral hemorrhage (ICH). Here, we constructed a mouse ICH model to investigate the changes in ICH-associated brain protein succinylation, following a treatment with a TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized the prevalence of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase of 29 succinyllysine sites on 28 succinylated proteins and a reduction of 24 succinyllysine sites on 23 succinylated proteins in the ICH brains. TAK242 treatment induced both protein hypersuccinylations and hyposuccinylations, which were mainly located in the mitochondria and cytoplasm. GO analysis showed that TAK242 treatment-induced changes in the ICH-associated succinylated proteins were mostly located in synapses, membranes and vesicles, and enriched in many cellular functions/compartments, such as metabolism, synapse, and myelin. KEGG analysis showed that TAK242-induced hyposuccinylation was mainly linked to fatty acid metabolism, including elongation and degradation. Moreover, a combined analysis of the succinylproteomic data with previously published transcriptome data revealed that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed throughout neurons, astrocytes, and endothelial cells, and the mRNAs of seven and three succinylated proteins were highly expressed in neurons and astrocytes, respectively. In conclusion, we revealed that several TLR4 signaling pathways affect the succinylation processes and pathways in mouse ICH brains, providing new insights on the ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622. [ABSTRACT FROM AUTHOR]

Aims Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. Methods and results Plasma TMAO levels were higher in patients with CAVD (n  = 69) than in humans without CAVD (n  = 263), as examined by liquid chromatography–tandem mass spectrometry. Western blot and staining probes showed that TMAO-induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress, and nuclear factor-κB (NF-κB) activation in vitro. Notably, the TMAO-mediated effects were reversed by the use of ER stress, mitochondrial stress, and NF-κB activation inhibitors and small interfering RNA. Mice treated with supplemental choline in a high-fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (an inhibitor of trimethylamine formation) treatment. Conclusions Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo. [ABSTRACT FROM AUTHOR]

Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota–gut–brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Elevated blood pressure (BP) is a risk factor for cognitive impairment.Objective: We aim to explore the association between the duration of hypertension in early adulthood, with cognitive function in midlife. Furthermore, we investigate whether this asssociation is altered among participants with controlled BP.Methods: This prospective study included 2,718 adults aged 18-30 years without hypertension at baseline who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Duration of hypertension was calculated based on repeat measurements of BP performed at 2, 5, 7, 10, 15, 20, and 25 years after baseline. Cognitive function was assessed at Year-25 using the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop test.Results: After multivariable adjustment, a longer hypertension duration was associated with worse verbal memory (RAVLT, p trend = 0.002) but not with processing speed (DSST, p trend = 0.112) and executive function (Stroop test, p trend = 0.975). Among subgroups of participants with controlled (BP < 140/90 mmHg) and uncontrolled (SBP≥140 mmHg or DBP≥90 mmHg) BP at the time of cognitive assessment (i.e., Year-25 BP), longer duration of hypertension was associated with worse verbal memory. Similar results were observed in subgroups with controlled and uncontrolled average BP prior to cognitive assessment.Conclusion: Longer duration of hypertension during early adulthood is associated with worse verbal memory in midlife regardless of current or long-term BP control status. The potential risk of hypertension associated cognitive decline should not be overlooked in individuals with a long duration of hypertension, even if BP levels are controlled. [ABSTRACT FROM AUTHOR]

Objective: We described our initial experience of a new integrated oncology phamaceutical care practice to enhance the quality of pharmacy service and patient care in Huashan hospital. Data sources: A retrospective study was performed from August 2019 to September 2020. Patients were described as integrated pharmacy service group and routine care group. Medication adherence of patients in integrated pharmacy service group was recorded by the online management system. Patient satisfaction and the cumulative incidence of emergency room (ER) and outpatient visit were evaluated between two groups. Data summary: In total, 323 patients received the integrating oncology pharmacy service. The percentage of the patients missing administration every day was reduced from 29.7% to 0.3% within a 40-day monitoring and intervention period. There was a significant difference on patient satisfaction with pharmacy service in two groups (P < 0.05). Fewer patients in the integrated pharmacy service group visited clinic and ER compared with routine care group (33.1% vs. 59.2%; P < 0.05). Conclusions: As a new practice model, the integrated program is adopted to provide patient care and ongoing monitoring for cancer patients. The practice model delivers high continuity of care for cancer patients and improves communication and collaboration between healthcare professionals and oncology patients. The practice also provides the potential of developing hospital pharmaceutical service and optimizing disease prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Microglial activation and phenotypic shift play vital roles in many neurological diseases. Runt-related transcription factor-1 (Runx1), which is localized on microglia, inhibits amoeboid microglial proliferation. Preliminary data have indicated that the interaction of Runx1 with the Notch1 pathway affects the hemogenic endothelial cell shift. However, little is known about the effect of Runx1 and the Notch1 signaling pathway on the phenotypic shift of microglia during neuroinflammation, especially in temporal lobe epilepsy (TLE). A mouse model of TLE induced by pilocarpine and the murine microglia cell line BV-2 were used in this study. The proportion of microglia was analyzed using flow cytometry. Western blot (WB) analysis and quantitative real-time polymerase chain reaction were used to analyze protein and gene transcript levels, respectively. Immunohistochemistry was used to show the distribution of Runx1. In the present study, we first found that in a male mouse model of TLE induced by pilocarpine, flow cytometry revealed a time-dependent M2-to-M1 microglial transition after status epilepticus. The dynamic expression patterns of Runx1 and the downstream Notch1/Jagged1/Hes5 signaling pathway molecules in the epileptic hippocampus were determined. Next, Runx1 knockdown by small interfering RNA in BV-2 cells strongly promoted an M2-to-M1 microglial phenotype shift and inhibited Notch1/Jagged1/Hes5 pathway expression. In conclusion, Runx1 may play a critical role in the M2-to-M1 microglial phenotype shift via the Notch1 signaling pathway during epileptogenesis in a TLE mouse model and in BV-2 cells. [ABSTRACT FROM AUTHOR]

Although most risk factors for cardiac valve calcification (VC) are similar to those for coronary artery disease (CAD), they differ regarding lesions and clinical symptoms. Recently, increasing evidence suggests that intestinal bacteria play essential roles in cardiovascular disease (CVD). It is plausible that the gut microbiota is linked to the occurrence of different CVDs under similar risk factors. Thus, we aimed to explore the gut microbiomes in patients with VC or CAD and determine their underlying connections. We collected samples from 119 subjects and performed 16S rRNA gene sequencing to analyze the gut microbiomes in VC and CAD patients and in control volunteers. The gut microbiomes of VC and CAD patients were significantly different in terms of beta-diversity. Bacteria from Veillonella dispar , Bacteroides plebeius and Fusobacterium were enriched in the VC group, while members of Collinsella aerofaciens , Megamonas , Enterococcus , Megasphaera , Dorea and Blautia were decreased. According to the association with dyslipidemia, seven operational taxonomic units (OTUs), including Parabacteroides distasonis, Megamonas , Fusobacterium , Bacteroides sp., Bacteroides plebeius, Lactobacillus and Prevotella copri , were regarded as potential pathogens for CVDs. Additionally, Prevotella copri might be a keystone of CVDs, especially in VC patients, while Collinsella aerofaciens is a possible keystone of CAD, based on the multi-correlations of these bacteria with other OTUs in microbial communities. Patients with VC and CAD suffer from different gut microbial dysbiosis. The gut microbiomes are associated with the clinical characteristics in these diseases and might be potential therapeutic targets. Image 1 • Cardiac valve calcification and coronary artery disease patients suffered from different gut microbial dysbiosis. • Prevotella copri [OTU568118] might be a potential therapeutic target for cardiac valve calcification. • Collinsella aerofaciens serve as an important operational taxonomic units "hub" in coronary artery disease. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) has been widely used in immunotherapy evaluation of patients with non-small cell lung cancer (NSCLC). However, the effect is not particularly ideal, and the association between PD-L1 and genetic alterations requires more exploration. Here, we performed targeted next-generation sequencing and PD-L1 immunohistochemistry (IHC) testing for PD-L1 expression on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) in 1549 patients. Our studies showed that surgical method of resection was positively correlated with IC+, and a low tumor mutation burden (TMB) was negatively correlated with TC+. Furthermore, we found that EGFR was mutually exclusive with both ALK and STK11. In addition, the features between PD-L1 expression status and genomic alterations were characterized. These results suggest that clinical characteristics and molecular phenotypes are associated with PD-L1 expression signatures, which may provide novel insights for improving the efficiency of immune checkpoint inhibitors (ICIs) in immunotherapy. • Genomic landscape and PD-L1 status of lung cancer tissues from 1549 patients • Identification of the correlation between genetic alterations and PD-L1 expression on TCs and ICs • Characterization of the correlation between clinical characteristics and PD-L1 expression on both TCs and ICs • These findings may provide valuable information for accurately focusing on the beneficiaries of ICIs during immunotherapy [ABSTRACT FROM AUTHOR]

Background and aims microRNA223 (miR-223) plays an important role in the development of atherosclerosis and ischemic stroke. It is involved in regulation of multiple physiological and pathophysiological processes such as cholesterol metabolism, endothelial cell (EC) function, and thrombosis. Here we investigated the role of methylation regulation of MIR-223 promoter region in atherosclerotic cerebral infarction (ACI) patients. Methods A total of 23 patients with ACI and 32 healthy individuals were recruited. We performed bisulfite sequencing PCR and real-time PCR to detect methylation levels of MIR-223 promoter region and miR-223, respectively, in genomic DNA isolated from peripheral blood leukocytes. Results Mean methylation levels of a total of nine CpGs of MIR-223 promoter were significantly lower in ACI patients than in healthy individuals ( p < 0.01), and were also significantly lower in individuals with carotid atherosclerosis than those without carotid atherosclerosis ( p < 0.05). Meanwhile, miR-223 expression in leukocytes was significantly higher in ACI patients than in healthy individuals ( p < 0.05). miR-223 level was negatively correlated with mean methylation levels of MIR-223 promoter ( r = −0.4451, p < 0.01). The methylation level of MIR-223 promoter revealed a positive correlation with the circulating total cholesterol level ( r = 0.318, p = 0.019). Conclusions Hypomethylation of MIR-223 promoter is associated with atherosclerotic cerebral infarction. [ABSTRACT FROM AUTHOR]

The Triassic Yidun arc belt (YAB) lies between the Jinshajiang suture zone to the west and the Garzê-Litang suture zone to the east, Eastern Tibetan Plateau. To study the YAB can not only help us to better understand the evolutionary history of the Garzê-Litang Ocean but can also provide some important information to constrain the evolution of the eastern Paleo-Tethys. In this paper, the geochronological and geochemical data of the Ganluogou dioritic complex were systematically investigated in order to decipher the geodynamic setting of the complex and to further determine the final closure time of the Garzê-Litang Ocean. The Ganluogou dioritic complex is located in the northern part of the YAB. It consists of ferrodiorite, diorite and a mixing zone between them and is the largest intermediate-mafic pluton in the YAB. The ferrodiorites were emplaced at 213 ± 2 Ma have low SiO 2 and high Fe 2 O 3 * contents, whereas the diorites formed at 209 ± 2 Ma and have relatively higher SiO 2 , Na 2 O + K 2 O, Th, U, Zr, and Hf contents, but lower Al 2 O 3 , MgO, CaO, Co, and Sr contents than the ferrodiorites. Relative to the primitive mantle both the ferrodiorites and diorites are depleted in Nb and Ta. However, the ferrodiorites exhibit strong depletion in Zr and Hf, whereas the diorites contain relatively higher Th and U contents without negative Zr and Hf anomalies. Both rock-types have similar chondrite-normalized rare earth element patterns with (La/Yb) N ratios = 4.4 to 18.2, and show weak Eu anomalies, with Eu/Eu* of 0.47 to 1. They both show narrow ranges in Sr–Nd–Hf isotopic compositions. However, the ferrodiorites contain lower initial 87 Sr/ 86 Sr ratios (0.7052–0.7057) and relatively higher ε Nd ( t ) values (− 3.8 to − 2.4) than the diorites, which record values of 0.7062–0.7066 and − 5.5 to − 5.7, respectively. For the zircon Hf isotopic composition, the ferrodiorites also exhibit higher 176 Hf/ 177 Hf ratios (0.282738–0.282804) and more depleted ε Hf ( t ) values (3.4–5.6) than those of the diorites ( 176 Hf/ 177 Hf ratios of 0.282690–0.282728 and ε Hf ( t ) values of 1.7–2.8). These geochemical and isotopic features suggest that the ferrodiorites and diorites were derived from the different magma sources. We propose that the ferrodiorites were produced by differentiation of mantle-derived tholeiitic arc magma, whereas the diorites were derived either from dehydration melting of meta-basaltic rocks from the Kangding Complex (the basement of the west Yangtze Craton) or young arc volcanic rocks but mixed with a small amount of sediments. Both ferrodiorites and diorites were emplaced at relatively low pressure (3.3–3.9 kbar) but with quite different magma temperature (ferrodiorites: 821–960 °C; diorites: 692–788 °C). The Ganluogou dioritic complex was therefore formed under an extension setting that was associated with the closure of the Garzê-Litang Ocean. Previous studies on Late Triassic magmatism in the area have shown that there was slab-break off event at ~ 216 Ma. Combined with regional geological background, we conclude that the final closure of the Garzê-Litang segment of the Paleo-Tethys Ocean occurred prior to 216 Ma. [ABSTRACT FROM AUTHOR]

Objective Understanding the neural mechanisms that support human consciousness is an important frontier in neuroscience and medicine. We previously developed a rodent model of temporal lobe seizures that recapitulates the human electroencephalography ( EEG) signature of ictal and postictal neocortical slow waves associated with behavioral impairments in level of consciousness. The mechanism of slow-wave production in epilepsy may involve suppression of the subcortical arousal systems including the brainstem and intralaminar thalamic nuclei. We hypothesized that intralaminar thalamic stimulation may lead to electrophysiologic and functional rescue from postictal slow waves and behavioral arrest. Methods We electrically stimulated the central lateral thalamic nucleus (a member of the intralaminar nuclei) under anesthesia and after electrically induced hippocampal seizures in anesthetized and in awake-behaving animal model preparations. Results We demonstrated a proof-of-principle restoration of electrophysiologic and behavioral measures of consciousness by stimulating the intralaminar thalamic nuclei after seizures. We measured decreased cortical slow waves and increased desynchronization and multiunit activity in the cortex with thalamic stimulation following seizures. Functionally, thalamic stimulation produced resumption of exploratory behaviors in the postictal state. Significance Targeting of nodes in the neural circuitry of consciousness has important medical implications. Impaired consciousness with epilepsy has dangerous consequences including decreased school/work performance, social stigmatization, and impaired airway protection. These data suggest a novel therapeutic approach for restoring consciousness after seizures. If paired with responsive neurostimulation, this may allow rapid implementation to improve level of consciousness in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Aim: The aim was to compare the efficacy and toxicity of paclitaxel plus platinum (TP) with gemcitabine plus platinum (GP) in untreated advanced non-small-cell lung cancer by a meta-analysis. Methods: An extensive literature search was performed for relevant randomized controlled trials. Studies were evaluated for eligibility and quality, and then the data were extracted and analyzed using Review Manager 5.1 software. Publication bias was evaluated according to Begg's funnel plot and Egger's test using Stata/SE version 10.1 software. Results: Six randomized controlled trials including 2,793 patients were ultimately identified. The meta-analysis demonstrated that the efficacy was comparable between TP and GP regimens according to the pooled relative risks (RRs) for overall response rate [0.99, 95 % confidence interval (CI) = 0.88-1.13, p = 0.92], disease control rate (0.96, 95 % CI = 0.90-1.03, p = 0.24) and 1-year survival (0.99, 95 % CI = 0.90-1.09, p = 0.87), and the hazard ratios for overall survival (1.06; 95 % CI = 1.00-1.13, p = 0.07) and time-to-progression of disease (1.05, 95 % CI = 0.97-1.14, p = 0.20). Grade 3-4 nausea or vomiting, anemia and thrombocytopenia were less frequent in the TP group (RR = 0.53, 95 % CI = 0.35-0.78, p = 0.002; RR = 0.37, 95 % CI = 0.30-0.45, p < 0.00001; RR = 0.20, 95 % CI = 0.14-0.27, p < 0.00001; respectively). Grade 3-4 sensory neuropathy, fatigue and neutropenia were comparable between the two groups. Sensitivity analyses in studies of paclitaxel compared with gemcitabine combined with the same platinum strengthened the above conclusion. Conclusions: Our meta-analysis showed that paclitaxel plus platinum had similar efficacy and less toxicity compared with gemcitabine plus platinum in first-line treatment of advanced non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Objective: Brain metastasis as the first symptom of lung cancer is a unique clinical entity. We conducted a retrospective study to investigate the clinical characteristics and survival of patients with lung cancer whose first symptom was brain metastases in an Asian population. Methods: A retrospective study of 186 such patients who had been admitted to one institution in China between January 1, 2003 and December 30, 2008 was performed. The following data were collected and analyzed: manifesting signs and symptoms, imaging studies, extracerebral metastases, initial diagnosis, treatment, and patient survival. Results: This sample population exhibited high rates of misdiagnosis upon initial presentation (46.8 %). Fifty-seven (30.6 %) patients presented with silent extracerebral metastases. Pathologies among this cohort varied, and adenocarcinomas were most commonly observed. Most patients received surgical resection, and some patients had additional whole-brain radiotherapy or stereotactic radiosurgery. The median survival time for the entire cohort was 15 months (95 % confidence interval, 12.9-17.1 months). Survival rates for 1, 2, and 5 years were 58.2, 34.2, and 6.5 %, respectively. The median survival time was 15, 14, 19, and 7 months for the gross total resection, incomplete resection, surgery + whole-brain radiotherapy, and surgery + stereotactic radiosurgery groups, respectively. Conclusions: Brain metastasis as the first symptom of lung cancer is a distinct clinical entity. Although overall survival was poor, combined treatments based on surgery for selected patients were reasonable with the exception of a minority who experienced long-term survival. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Whether platinum plus gemcitabine or vinorelbine are equally effective in the treatment of advanced non-small-cell lung cancer (NSCLC) is still controversial, a meta-analysis was performed to compare the gemcitabine plus platinum with vinorelbine plus platinum regimens in first-line treatment of advanced NSCLC. Methods: A literature search was performed in PubMed database, the Cochrane Central Register of Controlled Trials (CENTRAL) database, the Physician Data Query (PDQ) database, EMBASE and the American Society of Clinical Oncology (ASCO) annual meeting abstracts. The following keywords were used: “non small cell lung cancer,” or “Carcinoma, Non-Small-Cell Lung”. Reference lists of original articles and review articles were also examined. The published languages and years were not limited. The trials searched were evaluated for eligibility and quality, and then the data were abstracted and analyzed. Endpoints were overall survival, overall response, and toxicity. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Results: Nine randomized controlled trials involving 2186 patients were identified from 453 reports. They were all published as full-text articles. The intention-to-treatment (ITT) analysis demonstrated that the patients with gemcitabine plus platinum regimens had an equal overall response rate in comparison with vinorelbine plus platinum regimens (RR, 0.91; 95%CI, 0.81–1.03; P =0.15). Furthermore, the 1-year survival rate for the two platinum-based regimens were comparable (RR, 1.06; 95%CI, 0.96–1.18; P =0.27). Subgroup analysis comparing the cisplatin plus gemcitabine or vinorelbine had achieved the same results. Vinorelbine plus platinum regimens led to more frequent grade 3 or 4 of neutropenia, nephrotoxicity, constipation and phlebitis (OR, 0.37; 95%CI, 0.26–0.52; P <0.00001; OR, 0.38; 95%CI, 0.25–0.57; P <0.00001; OR, 0.50; 95%CI, 0.27–0.92; P =0.03 and OR, 0.13; 95%CI, 0.05–0.32; P <0.00001, respectively), while gemcitabine plus platinum chemotherapy inclined to developing more grade 3 or 4 thrombocytopenia (OR, 11.37; 95%CI, 4.56–28.38; P <0.00001). The incidence of grade 3 or 4 anemia, nausea and vomiting were almost comparable between the two arms (OR, 1.12; 95%CI, 0.62–2.02; P =0.71 and OR, 0.72; 95%CI, 0.41–1.28; P =0.27, respectively). Similar results were also achieved in subgroup analyses between the gemcitabine and vinorelbine in combination with the cisplatin. Conclusion: It could be concluded that the efficacy were similar between the platinum plus gemcitabine or vinorelbine regimens. The choice of platinum plus gemcitabine or vinorelbine depends on the toxicity of the drugs and patients’ tolerance. [Copyright &y& Elsevier]

Abstract: An alternate method of hierarchical classification combining Fisher discriminant analysis (FDA) and modified Sammon mapping (MSM) is presented in this paper. The FDA–MSM method could project most of the samples information for classification onto a new two or three dimensions object space and show the samples distribution directly. Meanwhile, the other part of the method for new sample classification within the object space is also provided, where a parameter P of rationality is defined to represent the degree of confidence that the new sample belongs to an assumed affiliated class, and the class which gets the highest rationality is the class in which the new sample belongs to. A dataset with seven classes to be discriminated was used to validate the proposed method. The methods used in the data analysis were the k-nearest neighbour (k-NN), back-propagation artificial neural network (BP-ANN), FDA, Sammon mapping and the FDA–MSM. The correct classification rates of all samples by k-NN, BP-ANN and FDA–MSM were 73.8, 97.6 and 98.8%, respectively. [Copyright &y& Elsevier]

Autophagy serves an important role in amyloid-β (Aβ) metabolism and τ processing and clearance in Alzheimer's disease. The progression of Aβ plaque accumulation and hyperphosphorylation of τ proteins are enhanced by oxidative stress. A hydrogen peroxide (H2O2) injury cell model was established using SH-SY5Y cells. Cells were randomly divided into normal, H2O2 and chlorogenic acid (5-caffeoylquinic acid; CGA) groups. The influence of CGA on cell viability was evaluated using a Cell Counting Kit-8 assay and cell death was assessed using Hoechst 33342 nuclear staining. Autophagy induction and fusion of autophagic vacuoles assays were performed using monodansylcadaverine staining. Additionally, SH-SY5Y cells expressing Ad-mCherry-green fluorescent protein-LC3B were established to detect autophagic flow. LysoTracker Red staining was used to evaluate lysosome function and LysoSensor™ Green staining assays were used to assess lysosomal acidification. The results demonstrated that CGA decreased the apoptosis rate, increased cell viability and improved cell morphology in H2O2-treated SH-SY5Y cells. Furthermore, CGA alleviated the accumulation of autophagic vacuoles, reduced the LC3BII/I ratio and decreased P62 levels, resulting in increased autophagic flux. Additionally, CGA upregulated lysosome acidity and increased the expression levels of cathepsin D. Importantly, these effects of CGA on H2O2-treated SH-SY5Y cells were mediated via the mTOR-transcription factor EB signaling pathway. These results indicated that CGA protected cells against H2O2-induced oxidative damage via the upregulation of autophagosomes, which promoted autophagocytic degradation and increased autophagic flux. [ABSTRACT FROM AUTHOR]

Ferulic acid, a main ingredient of Ligusticum, exhibits anti-oxidant and anti-inflammation effects in heart diseases. Some studies indicate that gut microbiome is associated with the generation of ferulic acid. Whether the beneficial effect of ferulic is raised by the alteration of gut microbiota is still unknown. This study examined the effect of sodium ferulate on gut microbiome and cardiac function in TAC mice. Cell Counting Kit-8 (CCK8) assay verified that ferulic acid has low toxicity in vitro and that ferulic acid inhibited the up-regulation of β-MHC and ANP induced by Angiotensin II. In addition, daily supplement of 50 mg/kg sodium ferulate improved the ejection fraction and changed the gut microbiota composition of TAC mice. Relative abundance of Lactobacillus and Parabacteroides are increased in TAC mice gavaged with sodium ferulate. In addition, Lactobacillus is negatively correlated with HW/BW and LW/BW ratio. These results suggest that the beneficial effect of ferulic in TAC mice is probably through the regulation of gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Driver gene-positive non-small cell lung cancer (NSCLC) patients are prone to develop leptomeningeal metastasis (LM), leading to an extremely high mortality. The objective of this study was to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) treatments for patients with NSCLC and LM harboring targetable mutations., Methods: We retrospectively collected records of patients with NSCLC harboring targetable mutations and prescribed ICIs following the diagnosis of LM at Huashan Hospital, Fudan University. In addition, we reviewed relevant literature and enrolled patients who met the inclusion criteria. Clinical characteristics were statistically analyzed, and the Kaplan-Meier method and log-rank test were employed to assess the median progression-free survival (mPFS) and median overall survival (mOS)., Results: A total of 37 patients with NSCLC harboring targetable mutations who received ICIs after LM diagnosis were included. The median age of the enrolled patients was 54 years (range, 33-70 years), and 62.2% were female. Following ICI administration, the intracranial objective response rate (iORR) and intracranial disease control rate (iDCR) for all enrolled patients were 18.9% and 62.2%, respectively. The mPFS of all patients was 2.5 months [95% confidence interval (CI): 2.166-2.834 months] and the mOS was 5.8 months (95% CI: 5.087-6.513 months). Both univariate and multivariate analyses revealed a significant increase in mOS or individuals who had previously undergone cranial radiation therapy compared to those who had not. Furthermore, different histology molecular types were found to be potentially associated with survival time., Conclusions: Some patients with NSCLC harboring targetable gene mutations following LM diagnosis may benefit from ICI treatment with relatively good tolerance. However, further screening of the most suitable patient populations for ICIs is required., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-477/coif). M.P. serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Aim: Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. Methods and Results: Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, Ldha specific knockout in astrocytes ( Aldh1l1 CreERT2 ; Ldha fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. Conclusion: Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Association between anti-GABA A R encephalitis and myasthenia gravis is extremely rare with few reported cases. Herein, we report a case of a female patient diagnosed with anti-GABA A R encephalitis and thymoma at the first admission. She was administered glucocorticoids for long-term immunotherapy, and thymectomy with biopsy demonstrated a type A thymoma. After 4 months, the symptoms of encephalitis were relieved, but she then developed post-thymectomy myasthenia gravis with anti-AChR and anti-titin dual positivity. Antibodies to connective tissue (anti-ANA, anti-PCNA) and those characteristics of paraneoplastic syndrome (anti-Ma2/Ta) were also positive. She received oral glucocorticoids and tacrolimus as immunosuppressive therapy, and myasthenic symptoms were stable during a 2-year follow-up. Our case revealed that anti-GABA A R encephalitis and myasthenia gravis can appear in patient with type A thymoma at different periods, which alerts physicians to take long-term follow-up for anti-GABA A R encephalitis with thymoma, even after thymectomy. Concurrent positivity for more than one antibody after thymectomy is rarely observed, and their contribution to the clinical course and treatment decision remains to be further investigated., (© 2023. Fondazione Società Italiana di Neurologia.)

Objective: This study aimed to evaluate the real-world clinical efficacy and safety, economic burdens and medical resource utilization (MRU) of toripalimab treatment patterns compared with bevacizumab plus chemotherapy (BCP) for patients with advanced non-squamous NSCLC in China., Methods: Progression-free survival (PFS), adverse drug reactions (ADR) and the costs of drugs, laboratory testing, imageology examinations (including CT, B ultrasound, MRI), medical service, nursing, treatment, genetic test and medical disposable material were compared between two groups. A retrospective observational study was conducted with electronic medical records from Fudan University Huashan hospital. Data was obtained from established electronic medical records (EMRs) and patient surveys. Survival time from the study enrollment to disease progression or death plus from 1st progression disease (PD) in the maintenance phase to 2nd PD (PFS II), adverse events (AE), direct medical costs, MRU and AE-related costs were collected and compared between toripalimab group and BCP group. A total of 246 patients were enrolled., Results: Toripalimab combination therapy has significantly prolonged PFS comparing with BCP (13.8 months vs. 6.2 months, p  < .001). A statistically significant improvement in PFS was observed favoring all toripalimab regimen subgroups compared with the bevacizumab group. Patients in toripalimab group occupied more overall resource consumption, more direct medical costs ($47,056.9 vs. $29,951.0, p  < .0001) and AE-related costs ($4,500.2 vs. $784.4, p  < .0001) than BCP group. Although patients in the toripalimab group used more drugs to prevent AEs ($4,500.2 vs. $784.4, p  < .0001), they still experienced more AEs than patients in BCP group (51.4% vs. 41.4%)., Conclusion: Toripalimab combination therapy could significantly prolonged PFS for patients with advanced non-squamous NSCLC compared with BCP, but at the expense of more MRU, costs and AEs.

Objective: Colorectal cancer (CRC) is a major global health concern, necessitating the identification of biomarkers and molecular subtypes for improved clinical management. This study aims to evaluate the clinical value of adipogenesis-related genes and molecular subtypes in CRC., Methods: A comprehensive analysis of adipogenesis-related genes in CRC was performed using publicly available datasets (TCGA and GEO database) and bioinformatics tools. Unsupervised cluster analysis was employed to identify the molecular subtypes of CRC, while LASSO regression analysis was utilized to develop a risk prognostic model. The immunogenomic patterns and immunotherapy analysis were used to predict patient response to immunotherapy. Furthermore, qPCR analysis was conducted to confirm the expression of the identified key genes in vitro., Results: Through the analysis of RNAseq data from normal and tumor tissues, we identified 50 differentially expressed genes. Unsupervised cluster analysis identified two subtypes (Cluster A and Cluster B) with significantly different survival outcomes. Cluster A and B displayed differential immune cell compositions and enrichment in specific biological pathways, providing insights into potential therapeutic targets. A risk-scoring model was developed using five ARGs, which successfully classified patients into high and low-risk groups, showing distinct survival outcomes. The model was validated and showed robust predictive performance. High-risk patients exhibited altered immune cell proportions and gene expression patterns compared to low-risk patients. In qPCR validation, four out of the five key genes were consistent with the results of bioinformatics analysis., Conclusion: Overall, the findings of our investigation offer valuable understanding regarding the clinical relevance of ARGs and molecular subtypes in CRC, laying the groundwork for improved precision medicine applications and personalized treatment modalities., (© 2023. The Author(s).)

Background: The purpose of this study was to investigate the potential involvement of pyruvate kinase M2 (PKM2), an enzyme acting as a rate-limiting enzyme in the final phase of glycolysis, in the regulation of glial activation and brain damage of intracerebral hemorrhage (ICH)., Methods: Western blotting and immunofluorescence were performed to investigate PKM2 expression, terminal deoxynucleotidyl transferase deoxyurinary triphosphate (dUTP) nick end labeling staining, hematoxylin and eosin staining, and behavioral tests were employed to evaluate the brain damage of ICH mice, and RNA-seq and bioinformatic analyses were performed to detect gene expression changes in ICH mice treated with TEPP-46., Results: Increased PKM2 levels in perihematomal brain tissue were found starting from 3 days following ICH and peaked at 5 and 7 days post ICH. The increased expression of PKM2 was mainly co-localized with glial fibrillary acidic protein (GFAP)+ astrocytes and ionized calcium binding adaptor molecule-1 (IBA-1)+ microglia. Furthermore, we observed a notable increase in the nuclear translocation of PKM2 in glial cells following ICH. TEPP-46 treatment significantly reduced PKM2 nuclear translocation, and effectively attenuated glial activation and brain injury, and improved functional recovery of mice with ICH. RNA-seq data indicated that 91.1% (205/225) of differentially expressed genes (DEGs) were down-regulated in the TEPP-46 treated groups compared with the vehicle-treated groups in ICH brains. Furthermore, bioinformatic analyses revealed that these down-regulated DEGs were involved in a variety of biological processes, including autophagy and metabolic processes. In addition, the majority of these downregulated DEGs had a primary high expression in neurons, with subsequent expression seen in endothelial cells, microglia, and astrocytes., Conclusions: These results indicate that increased PKM2 nuclear translocation promotes the activation of glial cells after ICH, hence aggravating ICH-induced brain damage, and aggravates the brain injury induced by ICH. This highlights a potential therapeutic target for inhibiting glial activation to attenuate brain injury after ICH., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

The paper introduces professor ZHUANG Li-xing 's clinical experience in treatment of dyskinesia of Parkinson's disease with acupuncture at triple-acupoint prescription. In pathogenesis, dyskinesia of Parkinson's disease refers to yang deficiency and disturbing wind. In treatment, acupuncture focuses on warming yang , promoting the circulation of the governor vessel, regulating the spirit and stopping trembling; and Baihui (GV 20), Suliao (GV 25) and Dingchanxue (Extra) are selected to be "trembling relief needling". In combination with Jin 's three needling, named "three-trembling needling" "three-governor-vessel needling" and "three-spasm needling", the triple-acupoint prescription is composed. To ensure the favorable therapeutic effect, this prescription is modified according to the symptoms and the specific techniques of acupuncture are combined such as conducting qi , harmonizing yin and yang , and manipulating gently for reinforcing and reducing.

Six new phloroglucinol derivatives, xanchryones I-N (1-6), were isolated from the leaves of Xanthostemon chrysanthus. Compounds 1-6 are unusual phloroglucinol-amino acid hybrids constructed through C 2 -N and O-C 1 ' bonds forming a peculiar oxazole ring. The structures and absolute configurations of compounds 1-6 were determined by MS, NMR, and single-crystal X-ray diffraction. Moreover, the anti-inflammatory and antibacterial activities of these compounds were evaluated., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Patients whose solid tumors (ST) show leptomeningeal metastasis (LM) have very poor prognosis and short overall survival. The aim of this study was to evaluate the efficacy of first-line programed death-1(PD-1) monoclonal antibody (mAb) treatment in these patients., Methods: We retrospectively evaluated patients diagnosed with LM from ST who were treated with first-line PD-1 mAb at our hospital between April 1 and November 30, 2019. We analyzed their clinicopathological characteristics and response to the treatment., Results: We collected and analyzed data from 6 patients with different primary ST. 5 patients received PD-1 mAb combined with chemotherapy and/or anti-angiogenic drugs, while one received only PD-1 mAb. The median (range) number of treatment cycles was 5.5 (1-21). PD-1 mAb treatment did not cause neurotoxicity. The time period of first assessment varied from 21 to 65 days after treatment. Among 5 patients who got obvious symptoms relief, 4 patients persisted for > 3 months and even showed a reduction in the number of tumor cells in cerebrosprinal fluid. Ventriculoperitoneal (VP) shunt was used to treat hydrocephalus observed beneficial in 3 patients: 2 before and 1 after PD-1 mAb treatment. The median (range) follow-up time was 214 (57-460) days. 4 patients died. The overall survival ranged from 57 days to at least 460 days. 1 of the two alive patients continued to show no worsening of symptoms after 457 days., Conclusions: Patients with LM from ST can benefit from first-line PD-1 mAb combined treatment without additional neurotoxicity. Further research is required to validate the safety and efficacy.

The brain metabolic changes caused by the interruption of blood supply are the initial factors of brain injury in ischemic stroke. Electroacupuncture (EA) pretreatment has been shown to protect against ischemic stroke, but whether its neuroprotective mechanism involves metabolic regulation remains unclear. Based on our finding that EA pretreatment significantly alleviated ischemic brain injury in mice by reducing neuronal injury and death, we performed a gas chromatography-time of flight mass spectrometry (GC-TOF/MS) to investigate the metabolic changes in the ischemic brain and whether EA pretreatment influenced these changes. First, we found that some glycolytic metabolites in the normal brain tissues were reduced by EA pretreatment, which may lay the foundation of neuroprotection for EA pretreatment against ischemic stroke. Then, 6[Formula: see text]h of cerebral ischemia-induced brain metabolic changes, especially the enhanced glycolysis, were partially reversed by EA pretreatment, which was manifested by the brain levels of 11 of 35 up-regulated metabolites and 18 of 27 down-regulated metabolites caused by cerebral ischemia significantly decreasing and increasing, respectively, due to EA pretreatment. A further pathway analysis showed that these 11 and 18 markedly changed metabolites were mainly involved in starch and sucrose metabolism, purine metabolism, aspartate metabolism, and the citric acid cycle. Additionally, we found that EA pretreatment raised the levels of neuroprotective metabolites in both normal and ischemic brain tissues. In conclusion, our study revealed that EA pretreatment may attenuate the ischemic brain injury by inhibiting glycolysis and increasing the levels of some neuroprotective metabolites.

Hepatitis B virus (HBV) infection is a major health burden worldwide, and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral trement. HBV core protein (HBc) has emerged as a promising antiviral target, as it plays important roles in critical steps of the viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains under debate. In this study, different approaches were used to address this question. In synthesized HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen (HBsAg) production in a hepatoma cell line and primary human hepatocytes. Reconstitution of HBc did not alter the expression of cccDNA-derived HBV markers. Similar results were obtained from an in vivo mouse model harboring cccDNA. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays revealed transcription regulation of HBc-deficient cccDNA chromatin similar to that of wild-type cccDNA. Furthermore, treatment with capsid assembly modulators (CAMs) dramatically reduced extracellular HBV DNA but could not alter viral RNA and HBsAg. Our results demonstrate that HBc neither affects histone modifications and transcription factor binding of cccDNA nor directly influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, they do not suppress cccDNA transcriptional activity. Thus, therapeutics targeting capsid or HBc should not be expected to sufficiently reduce cccDNA transcription. IMPORTANCE Hepatitis B virus (HBV) core protein (HBc) has emerged as a promising antiviral target. However, whether HBc can regulate HBV covalently closed circular DNA (cccDNA) transcription remains elusive. This study illustrated that HBc has no effect on epigenetic regulation of cccDNA, and it does not participate in cccDNA transcription. Given that HBc is dispensable for cccDNA transcription, novel cccDNA-targeting therapeutics are needed for an HBV cure.

Exosomes are critical mediators of intercellular communication. Exosomal circular RNAs (circRNAs) have been reported to play critical roles in the development of chemoresistance in various tumors, including gastric cancer. However, the role of exosomal circ&#95;0063526 in cisplatin (CDDP) resistance of gastric cancer is still unclear. The expression of circ&#95;0063526, microRNA-449a (miR-449a) and serine hydroxymethyltransferase 2 (SHMT2) mRNA was determined by quantitative real-time PCR (qRT-PCR). Cell viability was assessed by the Cell Counting Kit-8 assay. Cell migration and invasion were evaluated by the transwell assay and wound healing assay. Western blot assay was used to measure the protein expression of light Chain 3 (LC3) I/II, p62 and SHMT2. Exosomes were detected using transmission electron microscopy. The size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-449a and circ&#95;0063526 or SHMT2 was confirmed by a dual-luciferase reporter and RNA pull-down assays. Circ&#95;0063526 expression was increased in gastric cancer tissues and cells and CDDP-resistant cells. Extracellular circ&#95;0063526 could be packaged into exosomes and transmitted to sensitive cells, thus disseminating CDDP resistance. Knockdown of exosomal circ&#95;0063526 inhibited CDDP resistance via suppressing migration, invasion and autophagy in gastric cancer cells. Moreover, circ&#95;0063526 was identified as a molecular sponge of miR-449a to upregulate SHMT2 expression. Further, exosomal circ&#95;0063526 regulated SHMT2 expression to enhance CDDP resistance of gastric cancer cells. Additionally, high expression of exosomal circ&#95;0063526 in serum was associated with poor response to CDDP treatment in gastric cancer patients. Exosomal circ&#95;0063526 facilitated CDDP resistance in gastric cancer via regulating the miR-449a/SHMT2 axis., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Epilepsy is a chronic brain disease with recurrent seizures. Autophagy plays a crucial role in the progression of epilepsy. This study aimed to explore the function and intrinsic mechanism of the long non-coding RNA (lncRNA) UCA1/miR-132-3p/ATG16L1 axis in epilepsy via regulation of autophagy., Methods: The expression of lncRNA UCA1, miR-132-3p and ATG16L1 was measured in serum from epileptic patients by quantitative RT-PCR. A SH-SY5Y cell model was further constructed using retinoic acid to investigate the UCA1/ miR-132-3p/ATG16L1 axis by quantitative RT-PCR, western blotting, fluorescence in situ hybridisation, RNA immunoprecipitation, chromatin immunoprecipitation, and a dual-luciferase reporter gene assay., Results: In the serum of epileptic patients, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated, compared to controls. Similarly, in the SH-SY5Y cell model, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated in retinoic acid-treated cells; lncRNA UCA1 was mainly located in the cytoplasm. lncRNA UCA1 overexpression was shown to promote autophagic gene expression, which was reversed by miR-132-3p overexpression. Moreover, autophagic gene expression induced by miR-132-3p knockdown was reversed by ATG16L1 knockdown. Based on precipitation assays, lncRNA UCA1 and miR-132-3p were shown to form a complex with the transcription factor, EZH2, and miR-132-3p was shown to interact with ATG16L1 based on a luciferase assay. Finally, lncRNA UCA1 was shown to negatively regulate miR-132-3p expression, and miR-132-3p was shown to negatively regulate ATG16L1., Significance: In this cell model, lncRNA UCA1 promotes autophagic gene expression via epigenetic regulation mediated by ATG16L1 and miR-132-3p.

The drug-induced diverse response among patients is a severe problem for improving hemorheological character. However, there is no validated method for personalized therapy to the best of our knowledge. Here, we apply a gravity-driven deformability cytometry platform (GD-DCP) to profile the drug response of the red cell deformability (RCD) at the single-cell level using pentoxifylline (PTX) as a model drug, the effect of different concentrations of PTX (0, 2, 20, 200 μg mL -1 , the clinical dosage of PTX is 20 μg mL -1 ) on RCD in patients with cardiovascular disease was explored. Based on the GD-DCP, about 38 and 56% of the acute phase of acute myocardial infarction (AMI) patients in the acute phase and coronary heart disease (CHD) patients respond positively to PTX, respectively, indicating that PTX has a strong patient dependency on RCD. Moreover, RCD is observed to be significantly inversely correlated with the activation of membrane protein kinase C (PKC) as well as the concentration of Ca 2+ (both P < 0.001). The results of animal experiments show that the protective effects of PTX on myocardial ischemia rats have substantial individual variation, too. It is noted that the effect of PTX is highly consistent between RCD in vitro and in vivo outcomes (blood viscosity, myocardial injury, and electrocardiogram (ECG)) in the same rat. All these new findings suggest that the GD-DCP is a promising method that uses deformability in vitro as one of the important criteria in personalized medicine, and our study provides unique insight into the individual-dependent mechanisms of PTX for improving RCD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Non-small cell lung cancer (NSCLC) with Brain metastases (BM) is an advanced disease with poor prognosis and low survival rate. Our study evaluated the survival benefit of primary lung resection with mediastinal lymph node dissection in NSCLC patients with BM using Surveillance, Epidemiology, and End-result (SEER) databases., Methods: All cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with BM of NSCLC from 2010 to 2016 was retrospectively analyzed. Patients (N=203) patients who underwent radical surgical treatment for primary lung lesions and patients (N=15500) who did not undergo surgery were compared. We successfully analyzed patients using propensity score matching (PSM). Kaplan-Meier and Cox- regression analyses were applied to assess prognosis., Results: The median survival in the surgery group was longer than in the control group (27 months vs 5 months; P < 0.001) in the overall sample, 21 months longer compared to the control group (27 months vs 6 months; P<0.001) in a PSM cohort. Cox regression analysis showed that underwent surgery patients in the propensity-matched sample had a significantly lower risk of mortality (HR:0.243, 95%CI: 0.162-0.365, P < 0.001) compared with untreated patients. Multivariate analysis identified the following as independent risk factors for NSCLC with BM: no primary resection surgery, age >65 years, worse differentiation, squamous cell carcinoma, lymphatic metastasis, no systemic therapy. Subgroup analysis revealed that radical resection of the primary lung provided a survival benefit regardless of marital status, tumor size, tumor grade, tumor T stage, and mediastinal lymph node metastasis after PSM., Conclusion: Radical resection of primary lung can improve the survival of NSCLC patients with BM. Male, age>65years, poorly differentiated tumor, tumor size>5cm, and mediastinal lymph node metastasis were factors for poor survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that can be interpreted to mean that there is no potential conflict of interest., (Copyright © 2022 Wang, Li, Liang and Zhan.)

Objective: This study aimed to assess the association between triglyceride-glucose (TyG) index/homeostasis model assessment-insulin resistance (HOMA-IR) within young adults and congestive heart failure (CHF), and to explore whether TyG index can replace HOMA-IR as a surrogate marker for IR in predicting the risk of CHF., Methods: A total of 4,992 participants between the ages of 18 and 30 years were enrolled from the Coronary Artery Risk Development in Young Adults (CARDIA) investigation [from 1985 to 1986 (year 0)]. A Cox proportional hazard regression analysis was conducted for assessing correlations between baseline TyG index/HOMA-IR and CHF events, together with the receiver operating characteristic (ROC) curve employed for scrutinizing TyG index/HOMA-IR and the risk of CHF., Results: During the 31-year follow-up period, 64 (1.3%) of the 4,992 participants developed CHF. In multivariable Cox proportional hazards models, adjusted for confounding factors for CHF, an increased risk of CHF was associated with a per-unit increase in the TyG index [hazard ratio (HR) 2.8; 95% confidence interval (CI), 1.7-4.7] and HOMA-IR (HR 1.2; 95% CI, 1.1-1.3). A Kaplan-Meier curve analysis showed that participants in the TyG index and HOMA-IR index Q4 group had a higher risk of CHF than those in the Q1 group. The area under curve (AUC) for the TyG index and HOMA-IR consisted of 0.67 (95% CI, 0.6-0.742) and 0.675 (95% CI, 0.604-0.746), respectively. There were no significant differences between the TyG index and HOMA-IR for AUC ( p = 0.986)., Conclusion: The higher TyG index and HOMA-IR are independent risk factors for CHF. The TyG index can replace HOMA-IR in young adulthood as a surrogate marker for IR to predict the risk of CHF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Han, Zhou, Xue, Wang, Zhan, Bai, Huang, Zeng, Zhang, Ma, Ren and Xu.)

Four pairs of cinnamoyl-β-triketone derivative enantiomers, (+)- and (-)-xanthostones A-D ((+)- and (-)-1-4), were isolated from Xanthostemon chrysanthus. Compounds 1 and 2 feature a new rearranged cinnamoyl-phloroglucinol scaffold fused with a cinnamyl-β-triketone framework. Compounds 1, 3, and 4 are the first examples of natural products with a peculiar phenethyl-pyranone acid unit. Their structures with absolute configurations were determined by spectroscopic data, X-ray diffraction analysis and electronic circular dichroism (ECD) calculation. Interestingly, these novel compounds showed a tautomeric behavior in solution, which was revealed by NMR spectroscopy and density functional theory calculation. A plausible biosynthetic pathway toward xanthostones A-D was proposed. Additionally, the anti-inflammatory and antibacterial activities of xanthostones A-D were evaluated., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: To explore the association between dietary fiber and heart failure (HF)., Methods: Data were collected from the 2009-2018 National Health and Nutrition Examination Survey. Dietary fiber intake data were obtained from two 24-h dietary recall interviews. Logistic regression and restricted cubic spline models were used to explore the association of dietary intakes of total, cereal, fruit, and vegetable fiber with HF prevalence., Results: A total of 21869 adults were included in this study. After adjusting for multiple confounding factors, the odds ratios (OR) and 95% confidence intervals (CI) for HF was 0.49 (0.28 to 0.87, P for trend = 0.016) for the highest tertile versus lowest tertile of total fiber intake. Similar results were observed for cereal but not fruit and vegetable fiber intake. Dose-response analysis indicated that dietary intake of total and cereal fiber were inversely associated with HF in a linear manner., Conclusion: Intakes of total and cereal fiber were inversely associated with HF in adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor YH declared a shared affiliation with the authors at the time of review., (Copyright © 2022 Zhang, Lin, Chen, Gan, Zhou, Ma, Zeng, Xue, Wang, Zhan, Zeng and Xu.)

Aim: We aim to establish a predictive model for the evaluation of fecundity based on infertility-related factors., Methods: A total of 410 expectant couples who visited the First Affiliated Hospital of Xinjiang Medical University on January 1, 2017 and June 10, 2019 were included in this study. The 1-year follow-up was carried out to investigate the pregnancy of the female. They were divided into model group and test group, respectively. The basic information, life behavior and clinical indices were screened using the Logistics regression analysis and LASSO regression analysis. In addition, the multivariate logistic regression was used to establish the model for the prediction of fecundity risk., Results: The risk factors for the predictive model included female age and occupational pressure, gynecological disease, anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), fasting plasma glucose (FPG), depression, as well as male smoking. The area under the curve (AUC) for the model A and model B was 0.954 (0.931 ~ 0.978) and 0.955 (0.931 ~ 0.979), respectively. The AUC in the test group was 0.917 (0.869 ~ 0.965) and 0.921 (0.873 ~ 0.968). There were no statistical differences in the fitting value and measured values in the model group., Conclusions: We established a predictive model for the evaluation of fecundity, which showed a satisfactory accuracy and discriminatory power., (© 2022 Japan Society of Obstetrics and Gynecology.)

Aims: This study sought to investigate the association between blood pressure (BP) trajectories from early to middle adulthood and echocardiographic indices of structure and function in middle age., Methods and Results: This prospective cohort study included 4717 black and white adults aged 18-30 years at baseline (1985-86) who were followed over 30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Trajectories of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) from the Year 0 examination to Year 30 examination were identified using latent mixture modelling. Echocardiographic indices of myocardial structure, systolic function, and diastolic function were assessed at the Year 30 examination. Five distinct SBP trajectory groups were identified: low-stable [1110 participants (23.5%)], moderate-stable [2188 (46.4%)], high-stable [850 (18.0%)], moderate-increasing [416 (8.8%)], and high-increasing [153 (3.2%)]. After adjustment for clinical variables, a significant decreasing trend was observed from the high-increasing and moderate-increasing groups through to the low-stable group for left ventricular (LV) mass index [mean (SE): high-increasing, 112.3 (3.4); moderate-increasing, 99.3 (2.6); high-stable, 88.9 (2.5); moderate-stable, 86.1 (2.3); low-stable, 82.1 (2.4), P trend < 0.01], as well as LV end-diastolic dimension, left atrial volume index, and E/e', while an increasing trend was apparent for LV longitudinal strain, E/A ratio, and average e' velocities. Results were generally consistent for trajectories of DBP and PP., Conclusions: Higher BP trajectories from early to middle adulthood were associated with worse indices of myocardial modelling and LV systolic and diastolic function at middle age., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)