3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

A Convolutional Neural Network Model for Distinguishing Hemangioblastomas From Other Cerebellar-and-Brainstem Tumors Using Contrast-Enhanced MRI.

BACKGROUND: Hemangioblastoma (HB) is a highly vascularized tumor most commonly occurring in the posterior cranial fossa, requiring accurate preoperative diagnosis to avoid accidental intraoperative hemorrhage and even death. PURPOSE: To accurately distinguish HBs from other cerebellar-and-brainstem tumors using a convolutional neural network model based on a contrast-enhanced brain MRI dataset. STUDY TYPE: Retrospective. POPULATION: Four hundred five patients (182 = HBs; 223 = other cerebellar-and brainstem tumors): 305 cases for model training, and 100 for evaluation. FIELD STRENGTH/SEQUENCE: 3 T/contrast-enhanced T1-weighted imaging (T1WI + C). ASSESSMENT: A CNN-based 2D classification network was trained by using sliced data along the z-axis. To improve the performance of the network, we introduced demographic information, various data-augmentation methods and an auxiliary task to segment tumor region. Then, this method was compared with the evaluations performed by experienced and intermediate-level neuroradiologists, and the heatmap of deep feature, which indicates the contribution of each pixel to model prediction, was visualized by Grad-CAM for analyzing the misclassified cases. STATISTICAL TESTS: The Pearson chi-square test and an independent t-test were used to test for distribution difference in age and sex. And the independent t-test was exploited to evaluate the performance between experts and our proposed method. P value <0.05 was considered significant. RESULTS: The trained network showed a higher accuracy for identifying HBs (accuracy = 0.902 ± 0.031, F1 = 0.891 ± 0.035, AUC = 0.926 ± 0.040) than experienced (accuracy = 0.887 ± 0.013, F1 = 0.868 ± 0.011, AUC = 0.881 ± 0.008) and intermediate-level (accuracy = 0.827 ± 0.037, F1 = 0.768 ± 0.068, AUC = 0.810 ± 0.047) neuroradiologists. The recall values were 0.910 ± 0.050, 0.659 ± 0.084, and 0.828 ± 0.019 for the trained network, intermediate and experienced neuroradiologists, respectively. Additional ablation experiments verified the utility of the introduced demographic information, data augmentation, and the auxiliary-segmentation task. DATA CONCLUSION: Our proposed method can successfully distinguish HBs from other cerebellar-and-brainstem tumors and showed diagnostic efficiency comparable to that of experienced neuroradiologists. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

The development of a combined clinico-radiomics model for predicting post-operative recurrence in atypical meningiomas: a multicenter study.

PURPOSE: Atypical meningiomas could manifest early recurrence after surgery and even adjuvant radiotherapy. We aimed to construct a clinico-radiomics model to predict post-operative recurrence of atypical meningiomas based on clinicopathological and radiomics features. MATERIALS AND METHODS: The study cohort was comprised of 224 patients from two neurosurgical centers. 164 patients from center I were divided to the training cohort for model development and the testing cohort for internal validation. 60 patients from center II were used for external validation. Clinicopathological characteristics, radiological semantic, and radiomics features were collected. A radiomic signature was comprised of four radiomics features. A clinico-radiomics model combining the radiomics signature and clinical characteristics was constructed to predict the recurrence of atypical meningiomas. RESULTS: 1920 radiomics features were extracted from the T1 Contrast and T2-FLAIR sequences of patients in center I. The radiomics signature was able to differentiate post-operative patients into low-risk and high-risk groups based on tumor recurrence (P < 0.001). A clinic-radiomics model was established by combining age, extent of resection, Ki-67 index, surgical history and the radiomics signature for recurrence prediction in atypical meningiomas. The model achieved a good prediction performance with the integrated AUC of 0.858 (0.802-0.915), 0.781 (0.649-0.912) and 0.840 (0.747-0.933) in the training, internal validation and external validation cohort, respectively. CONCLUSIONS: The present study established a radiomics signature and a clinico-radiomics model with a favorable performance in predicting tumor recurrence for atypical meningiomas.

Analysis of the differential expression of serum miR-21-5p, miR-135-5p, and miR-155-5p by Bifidobacterium triplex viable capsules during the perioperative stage of colorectal cancer.

OBJECTIVE: In this study, we investigated the impact of perioperative administration of Bifidobacterium triplex viable capsules on the serum levels of circulating miR-21-5p, miR-135-5p, and miR-155-5p in patients with colorectal cancer (CRC). The purpose of this study is to provide a foundation for future research on the use of Bifidobacterium triplex viable capsules to enhance postoperative recovery in patients with CRC. METHODS: A total of 60 patients with primary CRC admitted to the Department of General Surgery at Shanxi Bethune Hospital between June 2020 and December 2020 were selected and randomly divided into two groups: 20 cases in the control group and 40 cases in the experimental group. The experimental group was administered oral Bifidobacterium triplex viable capsules during the perioperative period, while the control group was administered oral placebo. Before and after the perioperative period, the expression levels of miR-21-5p, miR-135-5p, and miR-155-5p were compared in the serum of both groups of patients. Furthermore, we established the prognostic value of these three miRNAs in CRC patients. RESULTS: After surgery, the expression levels of miR-21-5p, miR-135-5p, and miR-155-5p decreased in both groups of patients (P < 0.05). Significantly greater differences were observed between miR-21-5p and miR-135-5p (P < 0.001). Expression levels of serum miR-21-5p (P = 0.020) and miR-135-5p (P = 0.023) decreased significantly more in the experimental group than in the control group. The levels of the above three miRNAs after surgery did not correlate with 3-year OS (HR = 4.21; 95% CI 0.37-47.48; log-rank P = 0.20) or 3-year DFS (HR = 1.57; 95% CI 0.32-7.66; log-rank P = 0.55) in two groups. CONCLUSION: Radical surgery reduces the levels of serum miR-21-5p, miR-135-5p, and miR-155-5p expression in patients with CRC. The use of Bifidobacterium triplex viable capsules assists in achieving quicker perioperative recovery from radical surgery in CRC patients, and this underlying mechanism may be associated with the regulation of serum miR-21-5p, miR-135-5p, and miR-155-5p expression levels.

Tailoring the Electronic Metal-Support Interactions in Supported Silver Catalysts through Al modification for Efficient Ethylene Epoxidation.

Metal-modified catalysts have attracted extraordinary research attention in heterogeneous catalysis due to their enhanced geometric and electronic structures and outstanding catalytic performances. Silver (Ag) possesses necessary active sites for ethylene epoxidation, but the catalyst activity is usually sacrificed to obtain high selectivity towards ethylene oxide (EO). Herein, we report that using Al can help in tailoring the unoccupied 3d state of Ag on the MnO2 support through strong electronic metal-support interactions (EMSIs), overcoming the activity-selectivity trade-off for ethylene epoxidation and resulting in a very high ethylene conversion rate (~100 %) with 90 % selectivity for EO under mild conditions (170 °C and atmospheric pressure). Structural characterization and theoretical calculations revealed that the EMSIs obtained by the Al modification tailor the unoccupied 3d state of Ag, modulating the adsorption of ethylene (C2H4) and oxygen (O2) and facilitating EO desorption, resulting in high C2H4 conversion. Meanwhile, the increased number of positively charge Ag+ lowers the energy barrier for C2H4(ads) oxidation to produce oxametallacycle (OMC), inducing the unexpectedly high EO selectivity. Such an extraordinary electronic promotion provides new promising pathways for designing advanced metal catalysts with high activity and selectivity in selective oxidation reactions.

Loss of H3K27me3 expression enriches in recurrent grade 1&2 meningiomas and maintains as a biomarker stratifying progression risk.

PURPOSE: To determine if loss of H3K27me3 could predict higher risk of re-recurrence in recurrent meningiomas. METHODS: A retrospective, single-center cohort study was performed for patients who underwent resection of recurrent grade 1 (N = 132) &2 (N = 32) meningiomas from 2009 to 2013. Association of H3K27me3 staining and clinical parameters was analyzed. Additionally, H3K27me3 staining was performed from 45 patients whose tumors recurred and were resected during the follow-up, to evaluate H3K27me3 change during tumor progression. Survival analysis was performed as well. RESULTS: Loss of H3K27me3 expression was observed in 83 patients, comprising 63 grade 1 (47.7%) and 20 grade 2 patients (62.5%). Both grade 1 (p < 0.001) and grade 2 recurrent meningiomas (p < 0.001) had a higher frequency of H3K27me3 loss, compared to de novo meningiomas. 8 of 27 tumors with retained H3K27me3 lost H3K27me3 during re-recurrence (29.6%), while no gain of H3K27me3 was observed in progressive disease from 18 tumors with H3K27me3 loss. Loss of H3K27me3 expression was associated with an earlier re-recurrence in recurrent meningiomas grade 1 and 2 (p < 0.001), and was an independent prognostic factor for PFS in recurrent grade 1 meningiomas (p = 0.005). CONCLUSION: Compared to primary meningiomas, recurrent meningiomas more predominantly had loss of H3K27me3 expression, and further loss can occur during the progression of recurrent tumors. Our results further demonstrated that loss of H3K27me3 predicted shorter PFS in recurrent grade 1 and grade 2 meningiomas. Our work thus supports clinical testing of H3K27me3 in recurrent meningiomas WHO grade 1 and 2.

Histopathological auxiliary system for brain tumour (HAS-Bt) based on weakly supervised learning using a WHO CNS5-style pipeline.

PURPOSE: Classification and grading of central nervous system (CNS) tumours play a critical role in the clinic. When WHO CNS5 simplifies the histopathology diagnosis and places greater emphasis on molecular pathology, artificial intelligence (AI) has been widely used to meet the increased need for an automatic histopathology scheme that could liberate pathologists from laborious work. This study was to explore the diagnosis scope and practicality of AI. METHODS: A one-stop Histopathology Auxiliary System for Brain tumours (HAS-Bt) is introduced based on a pipeline-structured multiple instance learning (pMIL) framework developed with 1,385,163 patches from 1038 hematoxylin and eosin (H&E) slides. The system provides a streamlined service including slide scanning, whole-slide image (WSI) analysis and information management. A logical algorithm is used when molecular profiles are available. RESULTS: The pMIL achieved an accuracy of 0.94 in a 9-type classification task on an independent dataset composed of 268 H&E slides. Three auxiliary functions are developed and a built-in decision tree with multiple molecular markers is used to automatically formed integrated diagnosis. The processing efficiency was 443.0 s per slide. CONCLUSION: HAS-Bt shows outstanding performance and provides a novel aid for the integrated neuropathological diagnostic workflow of brain tumours using CNS 5 pipeline.

Correlations between intravoxel incoherent motion-derived fast diffusion and perfusion fraction parameters and VEGF- and MIB-1-positive rates in brain gliomas: an intraoperative MR-navigated, biopsy-based histopathologic study.

OBJECTIVES: To explore the correlations between histopathologic findings and intravoxel incoherent motion (IVIM)-derived perfusion and diffusion parameters in brain gliomas. METHODS: Thirty-two biopsy samples from twenty-one patients with newly diagnosed gliomas from a previous prospective cohort study were retrospectively analyzed. All patients underwent diffusion-weighted MRI with 22 b values (0-5000 s/mm2), followed by intraoperative MR-guided biopsy surgery and surgical resection. All 32 biopsy samples underwent immunohistochemical staining followed by quantitative analysis of cell density (cellularity), percent of MIB-1 (Ki67)-positive expression (pMIB-1), number of CD34-stained vessels (CD34-MVD), and percent of VEGF-positive expressing cells (pVEGF) using a multispectral phenotyping microscope. Based on the co-registered localized biopsy, correlation analysis was performed between the IVIM-derived biexponential model-based parameters (Dfast1500 and Dfast5000, Dslow1500 and Dslow5000, PF1500 and PF5000) and the above four pathological biomarkers and glioma grades. RESULTS: Significant positive correlations were revealed between Dfast5000 and pVEGF (rho (r) = 0.466, p = 0.007), and Dfast1500 and pVEGF (r = 0.371, p = 0.037). A significant negative correlation was revealed between PF5000 with pMIB-1 (r = - 0.456, p = 0.01). Moderate to good positive correlations were shown between Dfast5000 and glioma grades (r = 0.509, p = 0.003) and Dfast1500 and glioma grades (r = 0.476, p = 0.006). CONCLUSIONS: IVIM-DWI-derived Dfast and PF correlate, respectively, with intratumor pVEGF and pMIB-1. When using the wide-high b value scheme, IVIM-derived Dfast and PF tend to demonstrate better efficacy in evaluating malignancy-related characteristics such as angiogenesis and cellular proliferation in gliomas. KEY POINTS: • Intravoxel incoherent motion-diffusion-weighted imaging (IVIM-DWI)-derived fast diffusion (Dfast) and perfusion fraction (PF) can quantitatively reflect intratumor pVEGF and pMIB-1. • IVIM-DWI-derived Dfast and PF tend to demonstrate better efficacy in evaluating glioma malignancy when an optimized scheme is used. • IVIM-DWI-derived Dfast5000 and PF5000 are promising non-invasive parameters correlating with pVEGF and pMIB-1 in gliomas.

Predicting meningioma grades and pathologic marker expression via deep learning.

OBJECTIVES: To establish a deep learning (DL) model for predicting tumor grades and expression of pathologic markers of meningioma. METHODS: A total of 1192 meningioma patients from two centers who underwent surgical resection between September 2018 and December 2021 were retrospectively included. The pathological data and post-contrast T1-weight images for each patient were collected. The patients from institute I were subdivided into training, validation, and testing sets, while the patients from institute II served as the external testing cohort. The fine-tuned ResNet50 model based on transfer learning was adopted to classify WHO grade in the whole cohort and predict Ki-67 index, H3K27me3, and progesterone receptor (PR) status of grade 1 meningiomas. The predictive performance was evaluated by the accuracy and loss curve, confusion matrix, receiver operating characteristic curve (ROC), and area under curve (AUC). RESULTS: The DL prediction model for each label achieved high predictive performance in two cohorts. For WHO grade prediction, the area under the curve (AUC) was 0.966 (95%CI 0.957-0.975) in the internal testing set and 0.669 (95%CI 0.643-0.695) in the external validation cohort. The AUC in predicting Ki-67 index, H3K27me3, and PR status were 0.905 (95%CI 0.895-0.915), 0.773 (95%CI 0.760-0.786), and 0.771 (95%CI 0.750-0.792) in the internal testing set and 0.591 (95%CI 0.562-0.620), 0.658 (95%CI 0.648-0.668), and 0.703 (95%CI 0.674-0.732) in the external validation cohort, respectively. CONCLUSION: DL models can preoperatively predict meningioma grades and pathologic marker expression with favorable predictive performance. CLINICAL RELEVANCE STATEMENT: Our DL model could predict meningioma grades and expression of pathologic markers and identify high-risk patients with WHO grade 1 meningioma, which would suggest a more aggressive operative intervention preoperatively and a more frequent follow-up schedule postoperatively. KEY POINTS: WHO grades and some pathologic markers of meningioma were associated with therapeutic strategies and clinical outcomes. A deep learning-based approach was employed to develop a model for predicting meningioma grades and the expression of pathologic markers. Preoperative prediction of meningioma grades and the expression of pathologic markers was beneficial for clinical decision-making.

Exploring efficient hydrogen evolution electrocatalysts of nonmetal atom doped Mo2CO2 MXenes by first-principles screening.

Non-metal doping engineering has shown great potential for designing high-performance MXene-based catalysts for electrocatalytic hydrogen evolution. We rationally design 14 kinds of nonmetal atom-doped Mo2CO2 catalysts and investigate the effects of nonmetal doping on the thermal stability and hydrogen evolution reaction (HER) catalytic activity of these structures through first-principles calculations. The results show that the addition of nonmetal dopants, such as Si, Cl, Br and I, on the Mo2CO2 surface can effectively improve the HER activity, making them promising candidates for effective HER catalysts. Besides, we studied the thermal stability of nonmetal doped Mo2CO2 by calculating the binding energy and explored the reason behind the variation in the binding energy. Furthermore, the origin of the HER activity difference regulated by various nonmetal dopants is explained based on the analysis of their electronic properties. We found that the number of valence electrons and Bader charge coupling of doped nonmetal atoms are effective electronic descriptors of the hydrogen adsorption strength and HER activity, which provide a clue for future prediction of highly efficient MXene-based HER catalysts.

Refractive status and retinal morphology in children with a history of intravitreal ranibizumab for retinopathy of prematurity.

This study investigated the characteristics of refractive status, visual acuity, and retinal morphology in children with a history of receiving intravitreal ranibizumab for retinopathy of prematurity (ROP). Children 4-6 years of age were enrolled and divided into the following four groups: group 1, children with a history of ROP who had been treated with intravitreal ranibizumab; group 2, children with a history of ROP who had not received any treatment; group 3, premature children without ROP; and group 4, full-term children. Refractive status, peripapillary retinal nerve fiber layer (RNFL), and macular thickness were measured. A total of 204 children were enrolled. In group 1, myopic shift was not noted, but poorer best corrected visual acuity (BCVA) and shorter axial length were observed. Significantly lower peripapillary RNFL thickness in the average total and superior quadrant, higher central subfield thickness, lower parafoveal retinal thickness in average total, superior, and nasal and temporal quadrants were observed in group 1 than in the other groups. The poor BCVA in patients with ROP was correlated with the lower RNFL thickness in the superior quadrant.   Conclusion: Children with a history of type 1 ROP treated with ranibizumab did not show a myopic shift but did show abnormal retinal morphology and the poorest BCVA among all groups. We suggest that pediatric ophthalmologists should always pay attention to visual development in patients with ROP with a history of intravitreal ranibizumab. What is Known: • Anti-VEGF is efficiently and widely used in the treatment of type 1 retinopathy of prematurity (ROP), and different anti-VEGF agents are associated with different prevalence of myopia. • Patients with ROP who receive treatment such as laser therapy or cryotherapy have abnormal macular development and retinal nerve fiber layer (RNFL) thickness. What is New: • Children with a history of ROP treated with intravitreal ranibizumab did not show a myopic shift but did show poor BCVA at 4-6 years of age. • Abnormal macular morphology and lower peripapillary RNFL thickness were found in these children.

Initial screening for occult congenital ectopia lentis based on ocular biological parameters in preschool children.

BACKGROUND: This study aimed to identify an initial screening tool for congenital ectopia lentis (CEL) by comparing ocular biological parameters in children with myopia. METHODS: A retrospective case-control study was conducted at one tertiary referral centre, from October 2020 to June 2022. Axial length (AL), corneal curvature (CC), refractive astigmatism (RA), corneal astigmatism (CA), internal astigmatism (IA), the difference between the axis of RA and CA [AXIS(RA-CA)], white-to-white corneal diameter (WTW), and axial length-corneal radius ratio (AL/CR) were compared in 28 eyes of CEL patients, and 60 eyes of myopic patients matched for age and refraction. The spherical equivalent of each eye was < -3.00 D. Area under the curve (AUC) of the receiver operating characteristic curves were calculated. RESULTS: The differences in RA, AL, mean keratometry (Kmed), maximum keratometry (Kmax), minimum keratometry (Kmin), CA, IA, AXIS(RA-CA), WTW, and AL/CR between the CEL and myopic groups were statistically significant (p < 0.05; p < 0.001; p < 0.001; p < 0.001; p < 0.001; p < 0.05; p < 0.001; p < 0.001; p < 0.001; p < 0.001, respectively). In logistic regression analysis RA, IA, AXIS(RA-CA), and AL/CR were significantly associated with CEL (p < 0.05). AUCs for RA, IA, AXIS(RA-CA), and AL/CR were 0.694, 0.853, 0.814, and 0.960, respectively. AUCs for AL/CR in SE< -6.00 D subgroup was 0.970, and 0.990 in -6.00 D ≤ SE < -3.00 D group. An AL/CR < 3.024 was the optimal cut-off point differentiating the CEL and control groups (sensitivity, 92.9%; specificity, 88.30%). CONCLUSIONS: A smaller AL/CR could identify CEL in children with myopia. An AL/CR cut-off value of 3.024 may be the most sensitive and specific parameter for the differential diagnosis of CEL in patients with mild to high myopia.

Clinical Report: Correlation of Serum Vitamins and Chalazion.

SIGNIFICANCE: We demonstrate the clinical correlation between the vitamin A level with chalazion in East Chinese children. Vitamin A deficiency is likely to be a potential cause of childhood chalazion. PURPOSE: Chalazion is the most common lid inflammatory lesion of the eyelid, which can be caused by retention of tarsal gland secretions. Studies have revealed that vitamin deficiency is an essential risk factor for children with chalazion. In this study, we measured the serum levels of vitamin A and 25-hydroxyvitamin D (25(OH)D), in patients with chalazion. METHODS: The study included 180 subjects (90 patients with chalazion and 90 control healthy subjects) with an average age of 4.13 ± 2.01 years, and 47.8% of whom were female. Serums came from blood samples collected and used to measure the levels of vitamin A and 25(OH)D. RESULTS: Both groups had statistically similar baseline characteristics, including age and body mass index. The average serum vitamin A levels in patients with chalazion (0.54 ± 0.15 µmol/L) were significantly lower than in their control counterparts (0.60 ± 0.15 µmol/L; P = .01). There was no significant difference in the serum 25(OH)D levels between the patients (70.15 ± 19.73 nmol/L) and control subjects (71.64 ± 24.46 nmol/L). The percentage of vitamin A deficiency in chalazion group (52.2%) was much higher than the control counterparts (28.6%; P = .001). The percentage of 25(OH)D deficiency showed no significant difference between patients with chalazion and control subjects (58.9 vs. 56.7%). CONCLUSIONS: Low serum vitamin A was significantly associated with chalazion in children. The serum 25(OH)D level exhibited no correlation with chalazion.

[Diagnostic value of STAT6 immunohistochemistry in solitary fibrous tumor/meningeal hemangiopericytoma].

OBJECTIVE: To investigate the diagnostic role of STAT6 immunohistochemistry in solitary fibrous tumors (SFT)/meningeal hemangiopericytomas (HPC). METHOD: Evaluated the expression of STAT6, vimentin, CD34, EMA, PR, S-100, CD56, GFAP and Ki-67 in a cohort of 37 SFT/meningeal HPC, 30 meningiomas and 30 schwannomas by immunohistochemistry staining. RESULTS: All SFT/meningeal HPC demonstrated nuclear positivity for STAT6, and the proportion of positive tumor cells ranged from 60% to 95%, with no significant difference cases.Vimentin was strongly positive in all cases. CD34, EMA and PR positivity was found in 32 cases, 1 case and 4 cases, respectively.S-100 protein, CD56 and GFAP were negative; Ki-67 labeling index was 1%-8%. However, the meningiomas and schwannomas were negative for STAT6. CONCLUSIONS: STAT6 is a relatively specific biomarker for SFT/meningeal HPC, and may be used in the diagnosis and differential diagnosis of SFT/meningeal HPC, especially for the atypical cases, and allows the precise pathologic diagnosis of SFT/meningeal HPC.

The effect of pigeon yolk sac fluid on the growth behavior of calcium carbonate crystals.

Previous experiments have proved that thermodynamically unstable calcium carbonate vaterite can exist for long periods in the yolk sac of a pigeon embryo. The aim of this article was to demonstrate the effect of in vitro mineralization of yolk sac fluid on calcium carbonate by direct precipitation. Experiments were conducted using pigeon yolk sac fluid and using lecithin extracted from pigeon yolk sac fluid as a control to investigate the regulating effects of the organic components in the embryo on the formation of the calcium carbonate precipitate. Multiple characterization methods were employed to study the various morphological patterns, sizes, crystal growth, and crystal phase transformations of the calcium carbonate precipitates as regulated by the yolk sac fluid extracted at different stages of incubation. The experimental results demonstrate that as the incubation proceeds towards the later stages, the composition and environmental features of the yolk sac fluid become more favorable for the formation of relatively unstable calcium carbonate phases with high energies of the vaterite state. The experiments conducted with extracted lecithin as the template for crystal growth yielded similar results. A large amount of organic molecules with polar functional groups carried by the yolk sac fluid have strong effects and can both initially induce the crystallization and regulate the aggregation of calcium carbonate. Furthermore, this regulation process is found to be closely related to the lecithin contained in yolk sac fluid. These observations confirm the changes in yolk sac fluid composition during incubation have significant effects on the production of vaterite, which implicates the calcium transport during embryo growth.

Postnatal refinement of auditory hair cell planar polarity deficits occurs in the absence of Vangl2.

The distinctive planar polarity of auditory hair cells is evident in the polarized organization of the stereociliary bundle. Mutations in the core planar cell polarity gene Van Gogh-like 2 (Vangl2) result in hair cells that fail to properly orient their stereociliary bundles along the mediolateral axis of the cochlea. The severity of this phenotype is graded along the length of the cochlea, similar to the hair cell differentiation gradient, suggesting that an active refinement process corrects planar polarity phenotypes in Vangl2 knock-out (KO) mice. Because Vangl2 gene deletions are lethal, Vangl2 conditional knock-outs (CKOs) were generated to test this hypothesis. When crossed with Pax2-Cre, Vangl2 is deleted from the inner ear, yielding planar polarity phenotypes similar to Vangl2 KOs at late embryonic stages except that Vangl2 CKO mice are viable and do not have craniorachischisis like Vangl2 KOs. Quantification of planar polarity deficits through postnatal development demonstrates the activity of a Vangl2-independent refinement process that rescues the planar polarity phenotype within 10 d of birth. In contrast, the Pax2-Cre;Vangl2 CKO has profound changes in the shape and distribution of outer pillar cell and Deiters' cell phalangeal processes that are not corrected during the period of planar polarity refinement. Auditory brainstem response analyses of adult mice show a 10-15 dB shift in auditory threshold, and distortion product otoacoustic emission measurements indicate that this mild hearing deficit is of cochlear origin. Together, these data demonstrate a Vangl2-independent refinement mechanism that actively reorients auditory stereociliary bundles and reveals an unexpected role of Vangl2 during supporting cell morphogenesis.

Diagnosis and surgical treatment of cavernous sinus angioleiomyoma: a report of four cases.

OBJECTIVE: The aims of the study were to retrospectively evaluate the imaging characteristics of cavernous sinus angioleiomyoma and explore appropriate surgical approaches. METHODS: A total of four cases admitted to our hospital for repeated episodes of headache were enrolled. The common clinical manifestations included decreased vision, diplopia, blepharoptosis and facial numbness. The first three patients were misdiagnosed with cavernous sinus hemangioma, meningioma and chordoma, respectively. The fourth case was suspected to be angioleiomyoma. Imaging examination showed an oval-shaped tumor occupying the cavernous sinus. The tumor was hypointense on T1-weighted magnetic resonance imaging and extremely hyperintense on T2-weighted scan, which was similar to the cerebrospinal fluid, and was progressively enhanced from one side after gadolinium injection, pushing the internal carotid artery toward the inner side. RESULTS: Surgical resection was performed via an epidural approach for these four cases. Clinical symptoms were improved after surgery and no recurrence was observed during follow-up visits (average, 47.5 months). CONCLUSIONS: The initial symptom of cavernous sinus angioleiomyoma was repeated headache. The tumor seems extremely hyperintense on a T2-weighted image and expansive growth is pushing away the internal carotid artery rather than encasing it. It was progressively enhanced from one side after gadolinium injection. Surgical treatment based on an epidural approach had an excellent outcome in tumor resection and nerve protection.

Virtual formalin-fixed and paraffin-embedded staining of fresh brain tissue via stimulated Raman CycleGAN model.

Intraoperative histology is essential for surgical guidance and decision-making. However, frozen-sectioned hematoxylin and eosin (H&E) staining suffers from degraded accuracy, whereas the gold-standard formalin-fixed and paraffin-embedded (FFPE) H&E is too lengthy for intraoperative use. Stimulated Raman scattering (SRS) microscopy has shown rapid histology of brain tissue with lipid/protein contrast but is challenging to yield images identical to nucleic acid-/protein-based FFPE stains interpretable to pathologists. Here, we report the development of a semi-supervised stimulated Raman CycleGAN model to convert fresh-tissue SRS images to H&E stains using unpaired training data. Within 3 minutes, stimulated Raman virtual histology (SRVH) results that matched perfectly with true H&E could be generated. A blind validation indicated that board-certified neuropathologists are able to differentiate histologic subtypes of human glioma on SRVH but hardly on conventional SRS images. SRVH may provide intraoperative diagnosis superior to frozen H&E in both speed and accuracy, extendable to other types of solid tumors.

Presurgical Medical Treatment in Prolactinomas: Surgical Implications and Pathological Characteristics From 290 Cases.

OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). CONCLUSION: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

MRI-derived radiomics assessing tumor-infiltrating macrophages enable prediction of immune-phenotype, immunotherapy response and survival in glioma.

BACKGROUND: The tumor immune microenvironment can influence the prognosis and treatment response to immunotherapy. We aimed to develop a non-invasive radiomic signature in high-grade glioma (HGG) to predict the absolute density of tumor-associated macrophages (TAMs), the preponderant immune cells in the microenvironment of HGG. We also aimed to evaluate the association between the signature, and tumor immune phenotype as well as response to immunotherapy. METHODS: In this retrospective setting, total of 379 patients with HGG from three independent cohorts were included to construct a radiomic model named Radiomics Immunological Biomarker (RIB) for predicting the absolute density of M2-like TAM using the mRMR feature ranking method and LASSO classifier. Among them, 145 patients from the TCGA microarray cohort were randomly allocated into a training set (N=101) and an internal validation set (N=44), while the immune-phenotype cohort (N=203) and the immunotherapy-treated cohort (N=31, patients from a prospective clinical trial treated with DC vaccine) recruited from Huashan Hospital were used as two external validation sets. The immunotherapy-treated cohort was also used to evaluate the relationship between RIB and immunotherapy response. Radiogenomic analysis was performed to find functional annotations using RNA sequencing data from TAM cells. RESULTS: An 11-feature radiomic model for M2-like TAM was developed and validated in four datasets of HGG patients (area under the curve = 0.849, 0.719, 0.674, and 0.671) using MRI images of post contrast enhanced T1-weighted (T1CE). Patients with high RIB scores had a strong inflammatory response. Four hub-genes (SLC7A7, RNASE6, HLA-DRB1 and CD300A) expressed by TAM were identified to be closely related to the RIB, providing important evidence for biological interpretation. Only individuals with a high RIB score were shown to have survival benefits from DC vaccine [DC vaccine vs. Placebo: median progression-free survival (mPFS), 10.0 mos vs. 4.5 mos, HR=0.17, P=0.0056, 95%CI=0.041-0.68; median overall survival (mOS), 15.0 mos vs. 7.0 mos, HR=0.17, P =0.0076, 95%CI=0.04-0.68]. Multivariate analyses also confirmed that treatment by DC vaccine was an independent factor for improved survival in the high RIB score group. However, in the low RIB score group, DC vaccine was not associated with improved survival. Furthermore, a radiomic nomogram based on the RIB score and clinical factors could efficiently predict the 1-, 2-, and 3-year survival rates, as confirmed by ROC curve analysis (AUC for 1-, 2- and 3-year survival: 0.705, 0.729 and 0.684, respectively). CONCLUSIONS: The radiomic model could allow for non-invasive assessment of the absolute density of TAM from MRI images in HGG patients. Of note, our RIB model is the first immunological radiomic model confirmed to have the ability to predict survival benefits from DC vaccine in gliomas, thereby providing a novel tool to inform treatment decisions and monitor patient treatment course by radiomics.