Prevalence and risk factors for dementia and mild cognitive impairment among older people in Southeast China: a community-based study.

BACKGROUND: With the aging population, the number of individuals with dementia in China is increasing rapidly. This community-based study aimed to investigate the prevalence and risk factors for dementia and mild cognitive impairment (MCI) among older adults in China. METHODS: In this study, 20,070 individuals aged ≥ 65 were recruited between January 1, 2022, and February 1, 2023, from ten communities in Xiamen City, China. We collected data on age, sex, level of education, and medical history, as well as global cognition and functional status. The prevalence of dementia and MCI was examined, and the risk factors for different groups were assessed. RESULTS: The overall prevalence of dementia and MCI was approximately 5.4% (95% confidence interval [CI], 5.1-5.7) and 7.7% (95% CI, 7.4-8.1), respectively. The results also indicated that dementia and MCI share similar risk factors, including older age, female sex, hypertension, and diabetes mellitus. Compared with individuals with no formal education, those with > 6 years of education had an odds ratio for MCI of 1.83 (95% CI, 1.49-2.25). We also found that only 5.5% of the positive participants chose to be referred to the hospital for further diagnosis and treatment during follow-up visits. CONCLUSIONS: This study estimated the prevalence and risk factors for dementia and MCI among individuals aged ≥ 65 years in Southeast China. These findings are crucial for preventing and managing dementia and MCI in China.

Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma.

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 µM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 µM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

Concise Biothiol-Activatable HPQ-NBD Conjugate as a Targeted Theranostic Probe for Tumor Cells.

Cancer, as a malignant tumor, seriously endangers human health. The study of cancer diagnosis and therapy has great practical significance. The development of theranostic agents has become a very important research topic. Nevertheless, some existing agents still have imperfections, such as complex structures and difficult syntheses. Therefore, it is urgent for researchers to develop simple novel theranostic agents. In this study, the precipitated fluorophore HAPQ was used as a simple drug molecule for the first time and combined with NBD-Cl to construct a simple and efficient theranostic probe (HAPQ-NBD). The theranostic probe can distinguish between tumor cells and normal cells based on the higher levels of biothiol in tumor cells. In addition, the probe can use biothiol as a control switch to release higher levels of precipitated fluorophore HAPQ in tumor cells, leading to selective high toxicity to tumor cells, thus achieving the goal of selectively killing tumor cells. The construction of probe HAPQ-NBD provides a practical tool for the diagnosis and therapy of cancer. It is expected that the development and utilization of precipitated fluorophore will provide a new method and strategy for cancer diagnosis and therapy.

Single-view calibration of a catadioptric camera based on a theodolite model.

The catadioptric panoramic imaging system may provide 360° panoramic imaging by employing the convex surface of a quadric surface with rotational symmetry as the reflector, which effectively compensates for the disadvantages of the narrow field of view in typical camera systems. First, this paper proposes a theodolite-based catadioptric camera image model based on the rotational symmetry of a catadioptric camera mirror, which simplifies the 2D modeling problem to a 1D problem. Simultaneously, the equivalence of the theodolite imaging model and the standard spherical imaging model also is demonstrated in this work. Second, this paper presents a method to calibrate the theodolite model parameters using only a single view and explains the calculation of model parameter initialization and iterative optimization steps in detail. Then, this paper demonstrates how to calibrate the theodolite model parameters using only a single view, as well as how to calculate the model parameter initialization and iterative optimization steps. Finally, simulation experiments and actual experiments have confirmed the correctness and stability of the method. The experimental results show that the average and standard deviation of the back-projection error are, respectively, 0.1983125 pixels and 0.0006153 pixels, in this model. We believe the theodolite model suggested in this paper offers a viable approach to catadioptric camera image modeling.

Adsorption and Sensing Mechanism of a nTiO2 Particle (n = 1-3)-Doped MoTe2 Monolayer to Faulty and Hazardous Gases in the Underground Cableway.

With the rapid growth of the economy and industrial technology, vigoroso and stable power distribution networks have gradually been established worldwide. Among these networks, underground cables play a crucial role in the distribution process, determining the overall electrical stability of entire cities. Based on density functional theory, this paper first proposes a TiO2 particle-doped MoTe2 monolayer to detect and eliminate these faults and hazardous gases within the underground cableway. The band structure, total density of states, projected density of states, and differential charge density are analyzed. The results demonstrate that the presence of TiO2 particles significantly enhances the adsorption capacity of MoTe2, diminishes the electrical conductivity of the doping system, and heightens electron activity in the doping reaction zone. The best adsorption performance is achieved in the case of two-particle doping. Furthermore, the modified MoTe2 exhibits an enhanced capability for capturing SO2 and SOF2, with the adsorption mechanism classified as physical-chemical adsorption. This work not only introduces a novel surface modification method for a MoTe2 monolayer but also provides a substantial data set to support the design and production of efficient sensors used in the underground cableway. These contributions further enhance the safety and stability of power systems and ensure human health.

Spatial whole exome sequencing reveals the genetic features of highly-aggressive components in lung adenocarcinoma.

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes, especially the highly aggressive components. Based on a cohort of 5,933 patients, this study observed that in different tumor size groups, LUAD with MIP/SOL components showed a different prevalence, and patients with ALK alteration or TP53 mutations had a higher probability of developing MIP/SOL components. To control individual differences, this research used spatial whole-exome sequencing (WES) via laser-capture microdissection of five patients harboring these five coexistent components and identified genetic features among different histologic components of the same tumor. In tracing the evolution of components, we found that titin (TTN) mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by a cohort of 146 LUAD patients undergoing bulk WES. Functional analysis revealed that TTN mutations enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation. Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

Discovery of Novel Histone Deacetylase 6 (HDAC6) Inhibitors with Enhanced Antitumor Immunity of Anti-PD-L1 Immunotherapy in Melanoma.

A series of 2-phenylthiazole analogues were designed and synthesized as potential histone deacetylase 6 (HDAC6) inhibitors based on compound 12c (an HDAC6/tubulin dual inhibitor discovered by us recently) and CAY10603 (a known HDAC6 inhibitor). Among them, compound XP5 was the most potent HDAC6 inhibitor with an IC50 of 31 nM and excellent HDAC6 selectivity (SI = 338 for HDAC6 over HDAC3). XP5 also displayed high antiproliferative activity against various cancer cell lines including the HDACi-resistant YCC3/7 gastric cancer cells (IC50 = 0.16-2.31 µM), better than CAY10603. Further, XP5 (50 mg/kg) exhibited significant antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 63% without apparent toxicity. Moreover, XP5 efficiently enhanced the in vivo antitumor immune response when combined with a small-molecule PD-L1 inhibitor, as demonstrated by the increased tumor-infiltrating lymphocytes and reduced PD-L1 expression levels. Taken together, the above results suggest that XP5 is a promising HDAC6 inhibitor deserving further investigation.

Dynamic monitoring serum tumor markers to predict molecular features of EGFR-mutated lung cancer during targeted therapy.

To reveal the correlation of dynamic serum tumor markers (STMs) and molecular features of epidermal growth factor receptor-mutated (EGFR-mutated) lung cancer during targeted therapy, we retrospectively reviewed 303 lung cancer patients who underwent dynamic STM tests [neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 153 (CA153), the soluble fragment of cytokeratin 19 (CYFRA21-1), and squamous cell carcinoma antigen (SCC)] and circulating tumor DNA (ctDNA) testing with a panel covering 168 genes. At baseline, patients with EGFR mutation trended to have abnormal CEA, abnormal CA153, and normal SCC levels. Additionally, patients with Thr790Met (T790M) mutation were more likely to have abnormal CEA levels than patients without T790M mutation. Among patients with secondary resistance to EGFR tyrosine kinase inhibitors (TKI), the dynamic STMs showed a descending trend in the responsive stage and a rising trend in the resistant stage. However, the changing slopes differed between T790M subgroup and the non-T790M subgroup in individual STMs. Our study demonstrated that the combination of baseline levels and variations of STMs (including the responsive stage and resistant stage) can be suggestive of secondary EGFR-T790M mutation [area under the curve (AUC) = 0.897] and that changing trends of STMs (within 8 weeks after initiating the TKI therapy) can be potential predictors for the clearance of EGFR ctDNA [AUC = 0.871]. In conclusion, dynamic monitoring STMs can help to predict the molecular features of EGFR-mutated lung cancer during targeted therapy.

A genetic analysis of Chinese patients with early-onset Parkinson' s disease.

Genetic factors play an important role in early-onset Parkinson's disease (EOPD). The genetic spectrum of patients with EOPD varies widely among different ethnicities, with extensive investigations having been performed in Caucasian populations; however, research in Chinese populations remains limited. In this study, we performed multiplex ligation-dependent probe amplification assay and whole-exome sequencing in 15 unrelated Chinese EOPD patients with age of onset before 40 years. Among them, a patient carried compound heterozygous exon duplications in Parkin (exon 3 duplication and exon 4 duplication) (6.67 %) and two patients carried the homozygous pathogenic variant (p.D331Y) in PLA2G6 (13.33 %). Three novel variants in EIF4G1 (p.P1043S, p.R1505Q, and p.P266A) were identified and classified as uncertain significance. Additionally, a risk variant in GBA (p.L483P) was detected in one patient (6.67 %). PLA2G6 (13.33 %) was the most common causative gene among our EOPD patients. Furthermore, detailed clinical features were presented. Our results broaden the genetic spectrum and clinical phenotypic spectrum of EOPD patients.

Huangkui Capsule Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Macrophage Activation by Suppressing Inflammation and Oxidative Stress in Mice.

Background: Huangkui capsule (HKC) comprises the total flavonoid extract of flowers of Abelmoschus manihot (L.) Medicus. This study aimed to explore the effects of HKC on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and LPS-stimulated RAW 264.7 cells. Methods: Enzyme-linked immunosorbent assay, histopathology, spectrophotometry, and quantitative real-time polymerase chain reaction were used for the assessments. Statistical analysis was performed using a one-way analysis of variance. Results: LPS significantly increased lung inflammation, neutrophil infiltration, and oxidative stress and downregulated lung miR-451 expression. Treatment with HKC dramatically, reduced the total cell count in the bronchoalveolar lavage fluid (BALF), and inhibited myeloperoxidase activity in the lung tissues 24 h after LPS challenge. Histopathological analysis demonstrated that HKC attenuated LPS-induced tissue oedema and neutrophil infiltration in the lung tissues. Additionally, the concentrations of tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 in BALF and IL-6 in the plasma reduced after HKC administration. Moreover, HKC could enhance glutathione peroxidase and catalase activities and upregulate the expression of miR-451 in the lung tissues. In vitro experiments revealed that HKC inhibited the production of nitric oxide, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells and mouse primary peritoneal macrophages. Additionally, HKC downregulated LPS-induced transcription of TNF-α and IL-6 in RAW 264.7 cells. Conclusions: These findings suggest that HKC has anti-inflammatory and antioxidative effects that may protect mice against LPS-induced ALI and macrophage activation.

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis.

BACKGROUND: The responses of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing tumor cells. This study aims to evaluate the prognostic role of CD8+ TILs in cancer patients treated with ICIs. METHODS: We systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 12 Jul 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting efficacy and survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The study protocol is prospectively registered on PROSPERO (registration number CRD42021233654). FINDINGS: Findings: A total of 33 studies consisting of 2559 cancer patients were included. The result showed that high CD8+ TILs were significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41-0.67; p < 0.001), PFS (HR, 0.52; 95% confidence interval: 0.40-0.67; p < 0.001) and ORR (OR, 4.08; 95% confidence interval: 2.73-6.10; p  < 0.001) in patients treated with ICIs. Subgroup analyses suggested that patients with high CD8+ TILs had a better clinical benefit, regardless of different treatments (ICI mono therapy, or combination therapy), cancer types (NSCLC, melanoma and others), and CD8+ T cells locations (intra-tumor, stroma, and invasive margin). The higher baseline circulating CD8+ T cells from peripheral blood did not contribute to the improved OS (HR, 0.93; 95% confidence interval: 0.67-1.29; p = 0.67) and PFS (HR, 0.89; 95% confidence interval: 0.60-1.32; p = 0.56) compared with the low baseline. INTERPRETATION: Interpretation: Our results suggested that high intra-tumoral, stromal, or invasive marginal, but not circulating CD8+ T cells, can predict treatment outcomes in patients with ICIs therapy across different cancers, in either single-agent ICIs or combination with other therapies. FUNDING: Funding: China National Science Foundation (Grant No. 82,022,048, 81,871,893), Key Project of Guangzhou Scientific Research Project (Grant No. 201,804,020,030), High-level university construction project of Guangzhou medical university (Grant No. 20,182,737, 201,721,007, 201,715,907, 2,017,160,107); National key R & D Program (Grant No. 2017YFC0907903 & 2017YFC0112704) and the Guangdong high level hospital construction "reaching peak" plan.

Comparison of first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib) as adjuvant therapy in resected NSCLC patients with sensitive EGFR mutations.

BACKGROUND: Several randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting. METHODS: Early-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared. RESULTS: Of 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9-49.4), 42.8 months (95% CI, 29.6-97.8), and 32.5 months (95% CI, 23.9-49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib). CONCLUSIONS: This first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

Pin-pointing groundwater infiltration into urban sewers using chemical tracer in conjunction with physically based optimization model.

Groundwater infiltration into sanitary sewers increases hydraulic loadings of sewage collection systems and threatens wastewater treatment efficiency. However, cost-effective approach to quantify this important process still needs to be improved in order to better manage this common issue. This paper presents a method for determining the origin and amount of groundwater entering the urban sewer system. On a catchment scale, by measuring and tracking a chemical tracer (i.e., artificial sweetener acesulfame) in the urban sewers, the magnitude of daily groundwater flows in each sub-catchment could be quantified based on a Monte Carlo chemical mass balance approach. For the study site, 7.9% of the sewer length contributed 58% of the total groundwater infiltration. In the identified high-risk sub-catchment, groundwater sources and their spatial-temporal flows could be further pinpointed and elucidated by physically based numerical self-optimization model using microbial genetic algorithm method, which was verified by on-site sewer flow measurements, as well as time-series tracer concentration patterns at the terminal outlet. It was found that the diurnal variations of groundwater seepage into sewer network was linked to the in-pipe water level associated with sewage pumps operation mode, demonstrating the importance of in-pipe water level regulation in controlling groundwater infiltration. Compared with traditional visual inspection or direct flow measurement methods, the proposed approach exhibits distinct advantages in determining groundwater sources and flows in large sewer systems.

A Pathogenic Variant p.Phe177Val in PSEN1 Causes Early-Onset Alzheimer's Disease in a Chinese Family.

Familial Alzheimer's disease (FAD) present as a positive family history of cognitive decline, with early onset and an autosomal dominant inheritance pattern. FAD is mainly caused by the mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). In the present study, we identified a variant (c.529T > G, p.Phe177Val) in PSEN1 across three generations in a Chinese family with FAD using whole-exome sequencing. The mean age of onset was 39 years (range: 37 to 40 years) in this family. In cell transfection studies, the mutant PSEN1 protein carrying p.Phe177Val increased both the production of Aß42 and the ratio of Aß42 over Aß40, as compared to wild-type PSEN1. Our results confirm the pathogenicity of PSEN1 p.Phe177Val variant in FAD and broaden the clinical phenotype spectrum of FAD patients with PSEN1 p.Phe177Val variant.

Life cycle implications of urban green infrastructure.

Low Impact Development (LID) is part of a new paradigm in urban water management that aims to decentralize water storage and movement functions within urban watersheds. LID strategies can restore ecosystem functions and reduce runoff loadings to municipal water pollution control facilities (WPCF). This research examines the avoided energy and greenhouse gas (GHG) emissions of select LID strategies using life cycle assessment (LCA) and a stochastic urban watershed model. We estimate annual energy savings and avoided GHG emissions of 7.3 GJ and 0.4 metric tons, respectively, for a LID strategy implemented in a neighborhood in New York City. Annual savings are small compared to the energy and GHG intensity of the LID materials, resulting in slow environmental payback times. This preliminary analysis suggests that if implemented throughout an urban watershed, LID strategies may have important energy cost savings to WPCF, and can make progress towards reducing their carbon footprint.