Accurate assembly of thiophene-bridged titanium-oxo clusters with photocatalytic amine oxidation activity.

Designing and synthesizing well-defined crystalline catalysts for the photocatalytic oxidative coupling of amines to imines remains a great challenge. In this work, a crystalline dumbbell-shaped titanium oxo cluster, [Ti10O6(Thdc)(Dmg)2(iPrO)22] (Ti10, Thdc = 2,5-thiophenedicarboxylic acid, Dmg = dimethylglyoxime, iPrOH = isopropanol), was constructed through a facile one-pot solvothermal strategy and treated as a catalyst for the photocatalytic oxidative coupling of amines. In this structure, Thdc serves as the horizontal bar, while the {Ti5Dmg} layers on each side act as the weight plates. The molecular structure, light absorption, and photoelectrochemical properties of Ti10 were systematically investigated. Remarkably, the inclusion of the Thdc ligand, with the assistance of the Dmg ligand, broadens the light absorption spectrum of Ti10, extending it into the visible range. Furthermore, the effective enhancement of charge transfer within the Ti10 was achieved with the successful incorporation of the Thdc ligand, as opposed to PTC-211, where terephthalic acid replaces the Thdc ligand, while maintaining consistency in other aspects of Ti10. Building on this foundation, Ti10 was employed as a heterogeneous molecular photocatalyst for the catalytic oxidative coupling reaction of benzylamine (BA), demonstrating very high conversion activity and selectivity. Our study illustrates that the inclusion of ligands derived from Thdc enhances the efficiency of charge transfer in functionalized photocatalysts, significantly influencing the performance of photocatalytic organic conversion.

Incremental value of amyloid PET in a tertiary memory clinic setting in China.

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.

Intrinsic Defect-Driven Synergistic Synaptic Heterostructures for Gate-Free Neuromorphic Phototransistors.

The optoelectronic synaptic devices based on two-dimensional (2D) materials offer great advances for future neuromorphic visual systems with dramatically improved integration density and power efficiency. The effective charge capture and retention are considered as one vital prerequisite to realizing the synaptic memory function. However, the current 2D synaptic devices are predominantly relied on materials with artificially-engineered defects or intricate gate-controlled architectures to realize the charge trapping process. These approaches, unfortunately, suffer from the degradation of pristine materials, rapid device failure, and unnecessary complication of device structures. To address these challenges, an innovative gate-free heterostructure paradigm is introduced herein. The heterostructure presents a distinctive dome-like morphology wherein a defect-rich Fe7 S8 core is enveloped snugly by a curved MoS2 dome shell (Fe7 S8 @MoS2 ), allowing the realization of effective photocarrier trapping through the intrinsic defects in the adjacent Fe7 S8 core. The resultant neuromorphic devices exhibit remarkable light-tunable synaptic behaviors with memory time up to ≈800 s under single optical pulse, thus demonstrating great advances in simulating visual recognition system with significantly improved image recognition efficiency. The emergence of such heterostructures foreshadows a promising trajectory for underpinning future synaptic devices, catalyzing the realization of high-efficiency and intricate visual processing applications.

The impact of kidney function on plasma neurofilament light and phospho-tau 181 in a community-based cohort: the Shanghai Aging Study.

BACKGROUND: The blood-based biomarkers are approaching the clinical practice of Alzheimer's disease (AD). Chronic kidney disease (CKD) has a potential confounding effect on peripheral protein levels. It is essential to characterize the impact of renal function on AD markers. METHODS: Plasma phospho-tau181 (P-tau181), and neurofilament light (NfL) were assayed via the Simoa HD-X platform in 1189 dementia-free participants from the Shanghai Aging Study (SAS). The estimated glomerular filter rate (eGFR) was calculated. The association between renal function and blood NfL, P-tau181 was analyzed. An analysis of interactions between various demographic and comorbid factors and eGFR was conducted. RESULTS: The eGFR levels were negatively associated with plasma concentrations of NfL and P-tau181 (B = - 0.19, 95% CI - 0.224 to - 0.156, P < 0.001; B = - 0.009, 95% CI - 0.013 to -0.005, P < 0.001, respectively). After adjusting for demographic characteristics and comorbid diseases, eGFR remained significantly correlated with plasma NfL (B = - 0.010, 95% CI - 0.133 to - 0.068, P < 0.001), but not with P-tau181 (B = - 0.003, 95% CI - 0.007 to 0.001, P = 0.194). A significant interaction between age and eGFR was found for plasma NfL (Pinteraction < 0.001). In participants ≥ 70 years and with eGFR < 60 ml/min/1.73 m2, the correlation between eGFR and plasma NfL was significantly remarkable (B = - 0.790, 95% CI - 1.026 to - 0,554, P < 0.001). CONCLUSIONS: Considering renal function and age is crucial when interpreting AD biomarkers in the general aging population.

Microfluidics-Prepared Ultra-small Biomimetic Nanovesicles for Brain Tumor Targeting.

Blood-brain-barrier (BBB) serves as a fatal guard of the central nervous system as well as a formidable obstacle for the treatment of brain diseases such as brain tumors. Cell membrane-derived nanomedicines are promising drug carriers to achieve BBB-penetrating and brain lesion targeting. However, the challenge of precise size control of such nanomedicines has severely limited their therapeutic effect and clinical application in brain diseases. To address this problem, this work develops a microfluidic mixing platform that enables the fabrication of cell membrane-derived nanovesicles with precise controllability and tunability in particle size and component. Sub-100 nm macrophage plasma membrane-derived vesicles as small as 51 nm (nanoscale macrophage vesicles, NMVs), with a narrow size distribution (polydispersity index, PDI: 0.27) and a high drug loading rate (up to 89% for indocyanine green-loaded NMVs, NMVs@ICG (ICG is indocyanine green)), are achieved through a one-step process. Compared to beyond-100 nm macrophage cell membrane vesicles (general macrophage vesicles, GMVs) prepared via the traditional methods, the new NMVs exhibits rapid (within 1 h post-injection) and enhanced orthotopic glioma targeting (up to 78% enhancement), with no extra surface modification. This work demonstrates the great potential of such real-nanoscale cell membrane-derived nanomedicines in targeted brain tumor theranostics.

Structural, static, and dynamic functional MRI predictors for conversion from mild cognitive impairment to Alzheimer's disease: Inter-cohort validation of Shanghai Memory Study and ADNI.

Mild cognitive impairment (MCI) is a critical prodromal stage of Alzheimer's disease (AD), and the mechanism underlying the conversion is not fully explored. Construction and inter-cohort validation of imaging biomarkers for predicting MCI conversion is of great challenge at present, due to lack of longitudinal cohorts and poor reproducibility of various study-specific imaging indices. We proposed a novel framework for inter-cohort MCI conversion prediction, involving comparison of structural, static, and dynamic functional brain features from structural magnetic resonance imaging (sMRI) and resting-state functional MRI (fMRI) between MCI converters (MCI_C) and non-converters (MCI_NC), and support vector machine for construction of prediction models. A total of 218 MCI patients with 3-year follow-up outcome were selected from two independent cohorts: Shanghai Memory Study cohort for internal cross-validation, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort for external validation. In comparison with MCI_NC, MCI_C were mainly characterized by atrophy, regional hyperactivity and inter-network hypo-connectivity, and dynamic alterations characterized by regional and connectional instability, involving medial temporal lobe (MTL), posterior parietal cortex (PPC), and occipital cortex. All imaging-based prediction models achieved an area under the curve (AUC) > 0.7 in both cohorts, with the multi-modality MRI models as the best with excellent performances of AUC > 0.85. Notably, the combination of static and dynamic fMRI resulted in overall better performance as relative to static or dynamic fMRI solely, supporting the contribution of dynamic features. This inter-cohort validation study provides a new insight into the mechanisms of MCI conversion involving brain dynamics, and paves a way for clinical use of structural and functional MRI biomarkers in future.

Plasma p-tau217, p-tau181, and NfL as early indicators of dementia risk in a community cohort: The Shanghai Aging Study.

INTRODUCTION: Blood biomarkers showed values for predicting future cognitive impairment. Evidence from the community-based cohort was limited only in high-income countries. METHODS: This study included 1857 dementia-free community residents recruited in 2009-2011 and followed up in waves 2014-2016 and 2019-2023 in the Shanghai Aging Study. We intended to explore the relationships of baseline plasma ALZpath phosphorylated tau 217 (p-tau217), p-tau181, neurofilament light chain (NfL) with follow-up incident dementia, Alzheimer's disease (AD), and amyloidosis. RESULTS: Higher concentrations of plasma p-tau217, p-tau181, and NfL were correlated to higher decline speed of Mini-Mental State Examination score, and higher risk of incident dementia and AD. The p-tau217 demonstrated a significant correlation with longitudinal neocortical amyloid-beta (Aß) deposition (r = 0.57 [0.30, 0.76]) and a high accuracy differentiating Aß+ from Aß- at follow-ups (area under the receiver operating characteristic curve = 0.821 [0.703, 0.940]). DISCUSSION: Plasma p-tau217 may be an early predictive marker of AD and Aß pathology in older community-dwelling individuals.Highlights: Plasma p-tau217, p-tau181, and NfL were positively associated with long-term cognitive decline and risk of incident dementia.Plasma p-tau217 showed a better performance distinguishing Aß+ individuals from Aß- individuals at follow-ups.Plasma NfL may be a suitable predictor of general cognitive decline in older community-dwelling individuals.

Ce3+-Eu2+ Co-doped BaCa13Mg2(SiO4)8 cyan phosphor-ultra-high energy transfer efficiency for white light emitting diodes.

The energy transfer of Ce3+-Eu2+ can often greatly increase the luminescence efficiency and expand the scope of application. In this study, blue to cyan color-tunable phosphors BaCa13Mg2(SiO4)8:Ce3+,Eu2+ were prepared. BaCa13Mg2(SiO4)8:Eu2+ cyan phosphors have limited applications in WLEDs because of their disadvantages, including the inadequate luminescence performance and imperfect matching of UV chips. Therefore, Ce3+ ions were used as sensitizers to enhance the optical performance of Eu2+ ions. The energy transfer efficiency between Ce3+ and Eu2+ in the BaCa13Mg2(SiO4)8 host was calculated to be 96.7%, and the incorporation of Ce3+ ions boosted the integrated intensity and quantum efficiency of the emission spectrum by approximately 80% and 20%, respectively. At 140 °C, the integral emission intensities could still keep at 81.5% of the initial integral intensities at 25 °C. The Ce3+, Eu2+ co-doped cyan phosphor-based WLED lamp could produce outstanding warm white light with CIE coordinates of (0.3722, 0.3222), demonstrating the enormous potential for WLED applications.

Olfactory function, neurofilament light chain, and cognitive trajectory: A 12-year follow-up of the Shanghai Aging Study.

This study aimed to determine whether blood neurofilament light chain (NfL) modifies the association of olfactory dysfunction (OD) with long-term cognitive decline. A total of 1125 non-demented older adults in the Shanghai Aging Study were evaluated for baseline olfaction (12-item Sniffin' Sticks Smell Test) and cognitive trajectory by a 12-year follow-up. Baseline blood NfL was quantified using Single Molecular Array assay, and dichotomized into low and high levels based on the median value of concentration. The Mini-Mental State Examination (MMSE) and Telephone Interview for Cognitive Status-40 were used to assess participants' cognitive function. Cognitive decline was ascertained when dementia was diagnosed or documented in the medical record during follow-up, or the MMSE declining rate (slope) was 1.0 SD larger than the group mean. OD participants presented a steeper trajectory of MMSE score (p interaction = 0.004) and a high risk of cognitive decline (adjusted HR [95% CI], 1.82 [1.11, 2.98]) only in those with high NfL. Participants with combined OD and high NfL showed the highest risk of cognitive decline (adjusted HR, 2.43 [1.20, 4.92]). OD, especially in combination with high blood NfL concentration, may be able to identify individuals who later incur cognitive deterioration.

A metal-to-metal charge transfer induced green-yellow phosphor CsAlGe2O6:Bi3+ for full-spectrum LED devices.

With the development of solid-state lighting, full-spectrum lighting has gradually received extensive attention. Until now, Bi3+-doped narrow-band blue phosphors have been widely reported, but broadband green-yellow Bi3+-doped luminescent materials generated by metal-to-metal charge transfer have been rarely reported. In this study, a Bi3+ ion doped germanate luminescent material CsAlGe2O6:x%Bi3+ (1 ≤ x ≤ 11) is synthesized by a high-temperature sintering method. The phosphor can generate a broad green-yellow band peaking at 535 nm with a full width at half maximum of 165 nm under ultraviolet radiation. Through the analysis of the coordination environment, photoluminescence spectra and decay curves, the broadband emission spectra of Bi3+ ions are proved to be generated by the metal-to-metal charge transfer state and the 3P1 → 1S0 transition. By using theoretical research, luminescence kinetics, and Gaussian fitting, the luminescence mechanism of Bi3+ is examined. Meanwhile, the high quantum efficiency and superior thermal stability prove that the phosphor can be used as an efficient luminescent material in the field of full-spectrum LED devices.

Head-to-head comparison of plasma and PET imaging ATN markers in subjects with cognitive complaints.

BACKGROUND: Gaining more information about the reciprocal associations between different biomarkers within the ATN (Amyloid/Tau/Neurodegeneration) framework across the Alzheimer's disease (AD) spectrum is clinically relevant. We aimed to conduct a comprehensive head-to-head comparison of plasma and positron emission tomography (PET) ATN biomarkers in subjects with cognitive complaints. METHODS: A hospital-based cohort of subjects with cognitive complaints with a concurrent blood draw and ATN PET imaging (18F-florbetapir for A, 18F-Florzolotau for T, and 18F-fluorodeoxyglucose [18F-FDG] for N) was enrolled (n = 137). The ß-amyloid (Aß) status (positive versus negative) and the severity of cognitive impairment served as the main outcome measures for assessing biomarker performances. RESULTS: Plasma phosphorylated tau 181 (p-tau181) level was found to be associated with PET imaging of ATN biomarkers in the entire cohort. Plasma p-tau181 level and PET standardized uptake value ratios of AT biomarkers showed a similarly excellent diagnostic performance for distinguishing between Aß+ and Aß- subjects. An increased tau burden and glucose hypometabolism were significantly associated with the severity of cognitive impairment in Aß+ subjects. Additionally, glucose hypometabolism - along with elevated plasma neurofilament light chain level - was related to more severe cognitive impairment in Aß- subjects. CONCLUSION: Plasma p-tau181, as well as 18F-florbetapir and 18F-Florzolotau PET imaging can be considered as interchangeable biomarkers in the assessment of Aß status in symptomatic stages of AD. 18F-Florzolotau and 18F-FDG PET imaging could serve as biomarkers for the severity of cognitive impairment. Our findings have implications for establishing a roadmap to identifying the most suitable ATN biomarkers for clinical use.

AIEgens/Mitochondria Nanohybrids as Bioactive Microwave Sensitizers for Non-Thermal Microwave Cancer Therapy.

Aggregation-induced emission luminogens (AIEgens) are widely used as photosensitizers for image-guided photodynamic therapy (PDT). Due to the limited penetration depth of light in biological tissues, the treatments of deep-seated tumors by visible-light-sensitized aggregation-induced emission (AIE) photosensitizers are severely hampered. Microwave dynamic therapy attracts much attention because microwave irradiation can penetrate very deep tissues and sensitize the photosensitizers to generate reactive oxygen species (ROS). In this work, a mitochondrial-targeting AIEgen (DCPy) is integrated with living mitochondria to form a bioactive AIE nanohybrid. This nanohybrid can not only generate ROS under microwave irradiation to induce apoptosis of deep-seated cancer cells but also reprogram the metabolism pathway of cancer cells through retrieving oxidative phosphorylation (OXPHOS) instead of glycolysis to enhance the efficiency of microwave dynamic therapy. This work demonstrates an effective strategy to integrate synthetic AIEgens and natural living organelles, which would inspire more researchers to develop advanced bioactive nanohybrids for cancer synergistic therapy.

A novel efficient red-emitting K7SrY2B15O30: Eu3+ phosphor with non-concentration quenching and robust thermal stability for white LEDs.

Inhibiting energy migration between Eu3+ ions in a fixed host to get higher doping concentration is a permanent topic. Herein, a novel non-concentration quenching red-emitting K7SrY2-2xB15O30: xEu3+ (0.1 ≤ x ≤ 1.0) phosphor was synthesized via high-temperature sintering method. XRD measurement, Rietveld refinement results, and radius percentage deviation calculation demonstrated the phase purity and the occupation preference of Eu3+ ions. With continuously increasing doping Eu3+ ions, the absence of concentration quenching could be explained by long distance between two Eu3+ (7.012 Å) and the K7SrEu2B15O30 could exhibit striking photoluminescence performance with the highest emission wavelength centered at 617 nm. Meanwhile, under the radiation of 393 nm, the high internal quantum efficiency ( âˆ¼ 78.71 %), excellent color purity ( âˆ¼ 88.32 %) and robust thermal stability whose emission intensity at 140 °C could still reach âˆ¼ 97.31 % could guarantee its potential application. When coating BaMgAl10O17: Eu2+, (Ba, Sr)2SiO4: Eu2+, and K7SrEu2B15O30 on a near-ultraviolet chip, the bright white light with a low correlated color temperature of 4211 K and CIE color coordinates of (0.3675, 0.3556) could be obtained. Taking the analytic results above, the non-concentration quenching K7SrY2B15O30: Eu3+ compound has great potential to act as a candidate for red-emitting phosphors in solid-state lighting field.

Altered Gut Microbiota and Its Clinical Relevance in Mild Cognitive Impairment and Alzheimer's Disease: Shanghai Aging Study and Shanghai Memory Study.

Altered gut microbiota has been reported in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous research has suggested that specific bacterial species might be associated with the decline of cognitive function. However, the evidence was insufficient, and the results were inconsistent. To determine whether there is an alteration of gut microbiota in patients with MCI and AD and to investigate its correlation with clinical characteristics, the fecal samples from 94 cognitively normal controls (NC), 125 participants with MCI, and 83 patients with AD were collected and analyzed by 16S ribosomal RNA sequencing. The overall microbial compositions and specific taxa were compared. The clinical relevance was analyzed. There was no significant overall difference in the alpha and beta diversity among the three groups. Patients with AD or MCI had increased bacterial taxa including Erysipelatoclostridiaceae, Erysipelotrichales, Patescibacteria, Saccharimonadales, and Saccharimonadia, compared with NC group (p < 0.05), which were positively correlated with APOE 4 carrier status and Clinical Dementia Rating (correlation coefficient: 0.11~0.31, p < 0.05), and negatively associated with memory (correlation coefficient: −0.19~−0.16, p < 0.01). Our results supported the hypothesis that intestinal microorganisms change in MCI and AD. The alteration in specific taxa correlated closely with clinical manifestations, indicating the potential role in AD pathogenesis.

Plasma Aß42/Aß40 and p-tau181 Predict Long-Term Clinical Progression in a Cohort with Amnestic Mild Cognitive Impairment.

BACKGROUND: Previous studies reported the value of blood-based biomarkers in predicting Alzheimer disease (AD) progression among individuals with different disease stages. However, evidence regarding the value of these markers in those with amnestic mild cognitive impairment (aMCI) is insufficient. METHODS: A cohort with 251 aMCI individuals were followed for up to 8 years. Baseline blood biomarkers were measured on a single-molecule array platform. Multipoint clinical diagnosis and domain-specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression. RESULTS: Individuals with low Aß42/Aß40 and high p-tau181 at baseline demonstrated the highest AD risk (hazard ratio = 4.83, 95% CI 2.37-9.86), and the most dramatic decline across cognitive domains. Aß42/Aß40 and p-tau181, combined with basic characteristics performed the best in predicting AD conversion (AUC = 0.825, 95% CI 0.771-0.878). CONCLUSIONS: Combining Aß42/Aß40 and p-tau181 may be a feasible indicator for AD progression in clinical practice, and a potential composite marker in clinical trials.

Concordance of PD-L1 expression in triple-negative breast cancers in Chinese patients: A retrospective and pathologist-based study.

OBJECTIVE: To compare the expression of programmed cell death ligand 1 (PD-L1) in different paraffin blocks from the same triple-negative breast cancers (TNBC) specimen and between matched primary tumors and lymph node metastases (LNMets). We also aim to determine the interobserver agreement between pathologists trained on PD-L1 (SP142) assay in assessing TNBC. METHODS: 426 histologically confirmed TNBC cases, in which 85 have LNMets, were included in this study. A PD-L1 (SP142) assay was used to identify PD-L1 expression on tumor infiltrating immune cells (IC) and also on tumor cells (TC) in primary tumors and LNMets of TNBC by two trained pathologists. PD-L1 scoring and assessment were based on criteria in IMpassion 130 trial criteria. Concordance of PD-L1 expression in TNBC were analyzed using Kappa-test and assessed by the Kappa value. RESULTS: Prevalence of positive PD-L1 expression (PD-L1 +) on tumor-infiltrating immune cells (PD-L1 IC+) (IC≥1%) in LNMets (49.4%) was higher than in the matched primary tumors (38.9%). Concordance of PD-L1 expression on IC between the two paraffin blocks from the same primary tumor specimen was substantial (P < 0.000, Kappa = 0.627) and was identified in 83.1% (108/130) of the selected cases. For TNBC cases with matched primary and LNMets blocks, the concordance of PD-L1IC scoring between the two blocks was moderate (P < 0.000, Kappa = 0.434). Interobserver agreement of PD-L1 assessment was 78.2% (P < 0.000, Kappa = 0.567) in primary tumors and 61.4% (P < 0.000, Kappa = 0.253) in the matched LNets. CONCLUSION: Substantial intratumor concordance of PD-L1 scoring of the primary tumors in TNBC patients was determined, implying that immunohistochemically detection using one representative block of the primary tumor should be enough to assign the expression status of PD-L1 in clinical practice. The prevalence of PD-L1 + in lymph node metastases (LNMets) was higher than in the matched primary tumors, implying that PD-L1 detection in LNMets may provide additional PD-L1 expression information, especially in TNBC cases with PD-L1- in the matched primary breast tumors. Interobserver agreement of PD-L1 scoring in primary tumors was moderate while only fair in LNMets, implying that the additional training for PD-L1 assessment of TNBC LNMets specimens is recommended to enhance interobserver agreement. DATA AVAILABILITY: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

A 2-tier subdivision of papillary proliferations of the endometrium (PPE) only emphasizing the complexity of papillae precisely predicts the neoplastic risk and reflects the neoplasia-related molecular characteristics-a single-centered analysis of 207 cases.

Papillary proliferation of the endometrium (PPE) is subdivided based on the complexity of the papillae and the proliferation of lesions, and the complex group is considered to have an increased risk of concurrent/subsequent endometrial neoplasia. However, the current subdivision criteria fail to prove the equivalence of the quantity of simple papillae and structural complexity. In this study, we divided PPE of 207 cases from 2014 to 2022 into 3 groups according to structural complexity and proliferation degrees: Group 1 equaled to the simple PPE with a simple papillary structure and typical localized proliferation; group 2 had the simple structure similar to group 1 but occupy over 50% of the endometrial polyp or > 2 lesions in the surface of nonpolypoid endometrium; group 3 had the truly complex branching papillae despite of its proportion. Group 3 was implicated with significantly more concurrent endometrial neoplasia (EAH and carcinoma) compared with groups 1 and 2 (P < 0.01), while no difference was found between groups 1 and 2. In 128 cases with no concurrent endometrial abnormalities in the initial biopsy or curettage specimens, 4 cases presented endometrial neoplasia (3 carcinoma and 1 atypical hyperplasia) in the subsequent specimens, all of which presented PPE of group 3 but not group 1 or 2 in the prior tissues (P < 0.01). The immunochemistry of 83 cases showed similar expressions of ER, PTEN, ARID1A, PTEN, p16, ß-catenin, and p53 between PPE and the surrounding normal endometrium. Nearly 100% of PPE cases lost expressions of PR. A total of 2/83 cases showing PAX2 expression were all in the group 3 and correlated with endometrial neoplasia (2/17, 11.76%, P < 0.05). 76/83 (91.57%) of PPE lesions had KRAS mutations, and the distributions of which were similar among 3 groups. The frequency of mucinous metaplasia was significantly higher in the PPE lesions with KRAS mutations (72/74, 97.30%, P < 0.01). Group 3 showed higher frequency of single KRAS mutations compared with the combination of groups 1 and 2 (P < 0.01). Finally, the concordance of KRAS mutation profiles between PPE and endometrial neoplasia was significantly higher in group 3 than either group 1 or 2 (P < 0.01), while no difference was found between group 1 and 2. Thus, a new 2-tier subdivision system only emphasizing the complexity of papillae is recommended, which might precisely predict the risk of endometrial neoplasia and neoplasia-related molecular characteristics.

Extensive HPV Genotyping Reveals High Association between Multiple Infections and Cervical Lesions in Chinese Women.

Objective: The relationship between human papillomavirus (HPV) and cervical lesions has been extensively elucidated, but infection with multiple genotypes is less investigated due to methodology limitations. In the current study, with a method of genotyping 21 HPVs in a routine cervical screening population, we aimed to investigate the prevalence and diversity of HPV infections in Chinese women and further evaluate the impact of multiple infections of HPV on cervical lesion progression. Methods: Totally, 73,596 patients who underwent 21-genotype HPV testing from January 2018 to April 2019 were retrieved from the database of the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University. HPV testing was performed by real-time PCR assay, including 13 high-risk HPVs (hrHPV), 5 potential hrHPVs, and 3 low-risk HPVs. Results: Of the 17,079 (infection rate, 23.2%) hrHPV- or potential hrHPV- (hr/phrHPV-) positive cases, 26.3% had multiple infections. Women younger than 25 and older than 65 were more prone to multiple infections. Of the hr/phrHPV-positive cases involving cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+), HPV73, 53, and 66 (=59) were the top three genotypes most likely to be included in multiple infections, while HPV16, 18, and 58 were the 3 least. Patients with single infection of HPV16 had higher incidences of CIN2+ than those with multiple-infection pattern (P < 0.001), indicating that mixing with other genotypes alleviated pathogenicity. The infection of HPV52, 53, 56, 51, 39, 66, 59, 68, and 35 showed an opposite pattern, indicating that they were less likely to be pathogens individually. All other types showed no significant differences, indicating the capability of pathogenesis independently. HPV26 showed a higher OR for CIN2+ than most traditional hrHPV genotypes. The vial load and the percentage of HPV16 showed positive correlation with the severity of cervical lesions. Conclusion: Extensive genotyping identified 3 most frequent genotypes, HPV16, 52, and 58, in CIN2+ of Chinese population. HPV16 mixing with other genotypes alleviated its pathogenicity. The vial load and the percentage of HPV16 were positively correlated with the severity of cervical lesions. HPV26 may be considered as a hrHPV, which needs to be evaluated and confirmed by more cases.