Evaluation of the amelioration effect of Ganoderma formosanum extract on delaying PM2.5 damage to lung macrophages.

SCOPE: Particulate matter (PM) contains toxic organic matter and heavy metals that enter the entire body through blood flow and may cause mortality. Ganoderma formosanum mycelium, a valuable traditional Chinese medicine that has been used since ancient times, contains various active ingredients that can effectively impede inflammatory responses on murine alveolar macrophages induced by PM particles. METHODS AND RESULTS: An experimental study assessing the effect of G. formosanum mycelium extract's water fraction (WA) on PM-exposed murine alveolar macrophages using ROS measurement shows that WA reduces intracellular ROS by 12% and increases cell viability by 16% when induced by PM particles. According to RNA-Sequencing, western blotting, and real-time qPCR are conducted to analyze the metabolic pathway. The WA reduces the protein ratio in p-NF-κB/NF-κB by 18% and decreases the expression of inflammatory genes, including IL-1ß by 38%, IL-6 by 29%, and TNF-α by 19%. Finally, the identification of seven types of anti-inflammatory compounds in the WA fraction is achieved through UHPLC-ESI-Orbitrap-Elite-MS/MS analysis. These compounds include anti-inflammatory compounds, namely thiamine, adenosine 5'-monophosphate, pipecolic acid, L-pyroglutamic acid, acetyl-L-carnitine, D-mannitol, and L-malic acid. CONCLUSIONS: The study suggests that the WA has the potential to alleviate the PM -induced damage in alveolar macrophages, demonstrating its anti-inflammatory properties.

Pancreatic Ductal Adenocarcinoma: The Characteristics of Contrast-Enhanced Ultrasound Are Correlated with the Hypoxic Microenvironment.

A hypoxic microenvironment is associated with an increased risk of metastasis, treatment resistance and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). This study aimed to identify contrast-enhanced ultrasound (CEUS) characteristics that could predict the hypoxic microenvironment of PDAC. A total of 102 patients with surgically resected PDAC who underwent CEUS were included. CEUS qualitative and quantitative characteristics were analyzed. The expression of hypoxia-inducible factor-1α (HIF-1) and glucose transporter-1 (GLUT1) were demonstrated by immunohistochemistry. The associations between CEUS characteristics and the HIF-1α and GLUT1 expression of PDACs were evaluated. We found that HIF-1α-high PDACs and GLUT1-high PDACs had a larger tumor size and were more prone to lymph node metastasis. There was a significant positive linear correlation between the expression of HIF-1α and GLUT1. CEUS qualitative characteristics including completeness of enhancement and peak enhancement degree (PED) were related to the expression of HIF-1α and GLUT1. A logistic regression analysis showed that tumor size, lymph node metastasis, incomplete enhancement and iso-enhancement of PED were independent predictors for HIF-1α-high PDACs and GLUT1-high PDACs. As for quantitative characteristics, HIF-1α-high PDACs and GLUT1-high PDACs showed higher peak enhancement (PE) and wash-in rate (WIR). CEUS can effectively reflect the hypoxia microenvironment of PDAC, which may become a noninvasive imaging biomarker for prognosis prediction and individualized treatment.

Combining retinal structural and vascular measurements improves discriminative power for multiple sclerosis patients.

Data on how retinal structural and vascular parameters jointly influence the diagnostic performance of detection of multiple sclerosis (MS) patients without optic neuritis (MSNON) are lacking. To investigate the diagnostic performance of structural and vascular changes to detect MSNON from controls, we performed a cross-sectional study of 76 eyes from 51 MS participants and 117 eyes from 71 healthy controls. Retinal macular ganglion cell complex (GCC), retinal nerve fiber layer (RNFL) thicknesses, and capillary densities from the superficial (SCP) and deep capillary plexuses (DCP) were obtained from the Cirrus AngioPlex. The best structural parameter for detecting MS was compensated RNFL from the optic nerve head (AUC = 0.85), followed by GCC from the macula (AUC = 0.79), while the best vascular parameter was the SCP (AUC = 0.66). Combining structural and vascular parameters improved the diagnostic performance for MS detection (AUC = 0.90; p<0.001). Including both structure and vasculature in the joint model considerably improved the discrimination between MSNON and normal controls compared to each parameter separately (p = 0.027). Combining optical coherence tomography (OCT)-derived structural metrics and vascular measurements from optical coherence tomography angiography (OCTA) improved the detection of MSNON. Further studies may be warranted to evaluate the clinical utility of OCT and OCTA parameters in the prediction of disease progression.

Pan-mediastinal neoplasm diagnosis via nationwide federated learning: a multicentre cohort study.

BACKGROUND: Mediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODS: In this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGS: In the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATION: For mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Clinical Results, Risk Factors, and Future Directions of Ultrasound-Guided Percutaneous Microwave Ablation for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a relatively poor prognosis, especially for advanced HCC. With the availability of a variety of treatment options, the treatment strategies for HCC have become more and more diversified. Microwave ablation (MWA) has gradually been considered as a viable alternative to surgical resection (SR) owing to its comparable long-term survival, reduced complications, and greater preservation of hepatic parenchyma. However, clinical outcomes, tumor progression, and recurrence of HCC after MWA remain major concerns. Here, after reviewing the current therapeutic options for HCC, we focus on MWA, describing the advantages and challenges of MWA and the clinical results after treatment. We then focused on prognostic factors that influence post-ablation clinical outcomes and briefly presented the strategy of MWA for future clinical treatment.

Role of contrast-enhanced ultrasound with time-intensity curve analysis for differentiating hypovascular solid pancreatic lesions.

OBJECTIVES: To evaluate the clinical value of contrast-enhanced ultrasound (CEUS) with time-intensity curve (TIC) in distinguishing different types of hypovascular solid pancreatic lesions. METHODS: A total of 89 patients with 90 pancreatic lesions (all confirmed by surgery or biopsy pathology) that manifested hypoenhancement on contrast-enhanced ultrasound (CEUS) were included in this study. Six peak enhancement patterns were proposed for differentiating hypovascular pancreatic lesions. CEUS qualitative and TIC-based quantitative parameters were analyzed, and each lesion was scored based on the statistically significant qualitative parameters to evaluate the diagnostic ability of CEUS for hypovascular solid pancreatic lesions. RESULTS: Qualitative parameters such as peak enhancement pattern II/III/IV, penetrating vessels, centripetal enhancement, and early washout were reliable indicators of malignant lesions, and lesions scored based on these qualitative parameters, with a score ≥ 2, were highly suspected to be malignant lesions. Pattern I had an accuracy of 83.33% for predicting mass-forming pancreatitis (MFP), pattern V had an accuracy of 96.67% for predicting solid pseudopapillary tumors of the pancreas (SPTP), and pattern VI had an accuracy of 81.11% for predicting neuroendocrine tumors/carcinomas (NETs/NECs). For quantitative analysis, nodule/pancreatic parenchyma echo intensity reduction ratio was significantly greater in malignant lesions. CONCLUSIONS: CEUS qualitative and TIC-based quantitative parameters have clinical value in distinguishing malignant from benign hypovascular pancreatic lesions. KEY POINTS: • Contrast-enhanced ultrasound helps clinicians assess patients with pancreatic lesions. • Six peak enhancement patterns are proposed for differentiating pancreatic hypovascular lesions. • Qualitative parameters such as peak enhancement pattern II/III/IV, penetrating vessels, centripetal enhancement, early washout, and quantitative parameter nodule/pancreatic parenchyma echo intensity reduction ratio were important characteristics to discriminate malignant from hypovascular benign lesions.

Investigating the macular choriocapillaris in early primary open-angle glaucoma using swept-source optical coherence tomography angiography.

Introduction: There has been a growing interest in the role of vascular factors in glaucoma. Studies have looked at the characteristics of macular choriocapillaris in patients with glaucoma but with conflicting results. Our study aims to use swept-source optical coherence tomography angiography (SS-OCTA) to evaluate macular choriocapillaris metrics in normal participants and compare them with patients with early primary open-angle glaucoma (POAG) (mean deviation better than -6dB). Methods: In this prospective, observational, cross-sectional study, 104 normal controls (157 eyes) and 100 patients with POAG (144 eyes) underwent 3 mm × 3mm imaging of the macula using the Plex Elite 9000 (Zeiss Meditec, Dublin, CA, USA). Choriocapillaris OCTA images were extracted from the device's built-in review software and were subsequently evaluated for the density and size of choriocapillaris flow deficits. Results: After adjusting for confounding factors, the density of flow deficits was independently higher in those aged 53 years and above (P ≤ 0.024) whereas the average flow deficit size was significantly larger in those aged 69 years and above (95% CI = 12.39 to 72.91; P = 0.006) in both normal and POAG patients. There were no significant differences in the density of flow deficits (P = 0.453) and average flow deficit size (P = 0.637) between normal and POAG participants. Conclusion: Our study found that macular choriocapillaris microvasculature on SS-OCTA is unaltered by subjects with POAG. This suggests that OCTA macular choriocapillaris may not be potentially helpful in differentiating early glaucoma from healthy eyes.

Microvascular changes in the macular and parafoveal areas of multiple sclerosis patients without optic neuritis.

Retinal imaging has been proposed as a biomarker for neurological diseases such as multiple sclerosis (MS). Recently, a technique for non-invasive assessment of the retinal microvasculature called optical coherence tomography angiography (OCTA) was introduced. We investigated retinal microvasculature alterations in participants with relapsing-remitting MS (RRMS) without history of optic neuritis (ON) and compared them to a healthy control group. The study was performed in a prospective, case-control design, including 58 participants (n = 100 eyes) with RRMS without ON and 78 age- and sex-matched control participants (n = 136 eyes). OCTA images of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 Spectral-Domain OCT with AngioPlex OCTA, Carl Zeiss Meditec, Dublin, CA). The outcome variables were perfusion density (PD) and foveal avascular zone (FAZ) features (area and circularity) in both the SCP and DCP, and flow deficit in the CC. MS group had on average higher intraocular pressure (IOP) than controls (P < 0.001). After adjusting for confounders, MS participants showed significantly increased PD in SCP (P = 0.003) and decreased PD in DCP (P < 0.001) as compared to controls. A significant difference was still noted when large vessels (LV) in the SCP were removed from the PD calculation (P = 0.004). Deep FAZ was significantly larger (P = 0.005) and less circular (P < 0.001) in the eyes of MS participants compared to the control ones. Neither LV, PD or FAZ features in the SCP, nor flow deficits in the CC showed any statistically significant differences between the MS group and control group (P > 0.186). Our study indicates that there are microvascular changes in the macular parafoveal retina of RRMS patients without ON, showing increased PD in SCP and decreased PD in DCP. Further studies with a larger cohort of MS patients and MRI correlations are necessary to validate retinal microvascular changes as imaging biomarkers for diagnosis and screening of MS.

A multi-regression approach to improve optical coherence tomography diagnostic accuracy in multiple sclerosis patients without previous optic neuritis.

BACKGROUND: Optical coherence tomography (OCT) is a retinal imaging system that may improve the diagnosis of multiple sclerosis (MS) persons, but the evidence is currently equivocal. To assess whether compensating the peripapillary retinal nerve fiber layer (pRNFL) thickness for ocular anatomical features as well as the combination with macular layers can improve the capability of OCT in differentiating non-optic neuritis eyes of relapsing-remitting MS patients from healthy controls. METHODS: 74 MS participants (n = 129 eyes) and 84 age- and sex-matched healthy controls (n = 149 eyes) were enrolled. Macular ganglion cell complex (mGCC) thickness was extracted and pRNFL measurement was compensated for ocular anatomical factors. Thickness measurements and their corresponding areas under the receiver operating characteristic curves (AUCs) were compared between groups. RESULTS: Participants with MS showed significantly thinner mGCC, measured and compensated pRNFL (p ≤ 0.026). Compensated pRNFL achieved better performance than measured pRNFL for MS differentiation (AUC, 0.75 vs 0.80; p = 0.020). Combining macular and compensated pRNFL parameters provided the best discrimination of MS (AUC = 0.85 vs 0.75; p < 0.001), translating to an average improvement in sensitivity of 24 percent for differentiation of MS individuals. CONCLUSION: The capability of OCT in MS differentiation is made more robust by accounting OCT scans for individual anatomical differences and incorporating information from both optic disc and macular regions, representing markers of axonal damage and neuronal injury, respectively.

Nonhypovascular pancreatic ductal adenocarcinomas: CEUS imaging findings and differentiation from other types of solid pancreatic lesions.

OBJECTIVES: To observe and assess the diagnostic value of contrast-enhanced ultrasound (CEUS) in patients with iso-/hypervascular solid pancreatic lesions. METHODS: 70 pancreatic lesions (all confirmed by surgery or biopsy pathology) that manifested iso-/hyperenhancement on CEUS were retrospectively studied from January 2018 to January 2022, including 24 pancreatic ductal adenocarcinomas (PDAC), 15 mass-forming pancreatitis (MFP), 24 pancreatic neuroendocrine tumors (PNET) (14 hyper-PNETs, 10 iso-PNETs), and 7 solid pseudopapillary tumors of pancreas (SPTP). 65 pancreatic ductal adenocarcinomas (PDAC) that manifested hypoenhancement on CEUS were retrospectively studied from January 2020 to January 2022. CEUS patterns and the clinical and pathologic features were analyzed, and the diagnostic ability of CEUS for iso/hyperenhanced solid pancreatic lesions was assessed. RESULTS: Centripetal enhancement, heterogeneous enhancement, early washout, and hypoenhancement in the late phase mostly appeared in iso-/hyper-PDACs (p < 0.05). Heterogeneous enhancement in small lesions (< 3 cm) as the diagnostic criterion for iso-/hyper-PDACs had an accuracy of 74.3% and a specificity of 91.3%. Iso-PNETs more commonly had larger tumor sizes and more often showed heterogeneous enhancement than hyper-PNETs (p = 0.007, p = 0.035, respectively). The characteristics of the combination of isoenhancement, homogeneous enhancement, and synchronous wash-in/out for MFP had a high accuracy of 90%. Capsular enhancement with heterogeneous enhancement inside for SPTP had an accuracy of 97.1%. CONCLUSION: CEUS enhancement patterns have potentially great value in the differentiation of iso-/hyperenhanced pancreatic lesions.

Relationship of Quantitative Retinal Capillary Network and Myocardial Remodeling in Systemic Hypertension.

Background This study examined the associations between quantitative optical coherence tomography angiography (OCTA) parameters and myocardial abnormalities as documented on cardiovascular magnetic resonance imaging in patients with systemic hypertension. Methods and Results We conducted a cross-sectional study of 118 adults with hypertension (197 eyes). Patients underwent cardiovascular magnetic resonance imaging and OCTA (PLEX Elite 9000, Carl Zeiss Meditec). Associations between OCTA parameters (superficial and deep retinal capillary density) and adverse cardiac remodeling (left ventricular mass, remodeling index, interstitial fibrosis, global longitudinal strain, and presence of left ventricular hypertrophy) were studied using multivariable linear regression analysis with generalized estimating equations. Of the 118 patients with hypertension enrolled (65% men; median [interquartile range] age, 59 [13] years), 29% had left ventricular hypertrophy. After adjusting for age, sex, systolic blood pressure, diabetes, and signal strength of OCTA scans, patients with lower superficial capillary density had significantly higher left ventricular mass (ß=-0.150; 95% CI, -0.290 to -0.010), higher interstitial volume (ß=-0.270; 95% CI, -0.535 to -0.0015), and worse global longitudinal strain (ß=-0.109; 95% CI, -0.187 to -0.032). Lower superficial capillary density was found in patients with hypertension with replacement fibrosis versus no replacement fibrosis (16.53±0.64 mm-1 versus 16.96±0.64 mm-1; P=0.003). Conclusions We showed significant correlations between retinal capillary density and adverse cardiac remodeling markers in patients with hypertension, supporting the notion that the OCTA could provide a non-invasive index of microcirculation alteration for vascular risk stratification in people with hypertension.

MACULAR SENSITIVITY AND CAPILLARY PERFUSION IN HIGHLY MYOPIC EYES WITH MYOPIC MACULAR DEGENERATION.

PURPOSE: To evaluate the interrelationship between macular sensitivity and retinal perfusion density (PD) in eyes with myopic macular degeneration (MMD). METHODS: One hundred and thirty-eight highly myopic eyes from 82 adult participants were recruited. Macular sensitivity was evaluated using the Microperimeter MP-3. Retinal PD was measured using the PLEX Elite 9000 swept source optical coherence tomography angiography. Macular sensitivity values between different categories of MMD and its relationship with optical coherence tomography angiography measurements were evaluated using multivariable linear mixed models, adjusting for age and axial length. RESULTS: Macular sensitivity reduced with increasing severity of MMD (ß ≤ -0.95, P < 0.001), whereas the best-corrected visual acuity was not associated with MMD severity (P > 0.04). Persons who were older (ß = -0.08, P < 0.001), with longer axial length (ß = -0.32, P = 0.005), presence of macular diffuse choroidal atrophy (ß = -2.16, P < 0.001) or worse MMD (ß = -5.70, P < 0.001), and presence of macular posterior staphyloma (ß ≤ -2.98, P < 0.001) or Fuchs spot (ß = -1.58, P = 0.04) were associated with reduced macular sensitivity. Macular sensitivity was significantly associated with deep retinal PD in MMD (ß = 0.15, P = 0.004) but not with superficial retinal PD (P = 0.62). CONCLUSION: There was a strong correlation between reduced macular sensitivity and increasing MMD severity, even in mild MMD independent of the best-corrected visual acuity. Furthermore, macular sensitivity was correlated with deep retinal PD, suggesting a vasculature-function relationship in MMD.

Effect of hyperoxia and hypoxia on retinal vascular parameters assessed with optical coherence tomography angiography.

PURPOSE: To investigate the response of the superficial and deep capillary plexuses to hyperoxia and hypoxia using optical coherence tomography angiography (OCT-A) and retinal vessel analyzer. METHODS: Twenty-four healthy volunteers participated in this randomized, double-masked, cross-over study. For each subject, two study days were scheduled: on one study day, hyperoxia was induced by breathing 100% oxygen whereas on the other study day, hypoxia was induced by breathing a mixture of 88% nitrogen and 12% oxygen. Perfusion density was calculated in the superficial vascular plexus (SVP) and the deep capillary plexus (DCP), using OCT-A before (normal breathing) and during breathing of the gas mixtures. Retinal vessel calibres in major retinal vessels were measured using a dynamic vessel analyzer. RESULTS: During 100% oxygen breathing, a significant decrease in DCP perfusion density from 41.7 ± 2.4 a.u to 35.6 ± 3.1 a.u. (p < 0.001) was observed, which was accompanied by a significant decrease in vessel diameters in major retinal arteries and veins (p < 0.001 each). No significant change in perfusion density in the SVP occurred (p = 0.33). In contrast, during hypoxia, perfusion density in the SVP significantly increased from 34.4 ± 3.0 a.u. to 37.1 ± 2.2 a.u. (p < 0.001), while it remained stable in the DCP (p = 0.25). A significant increase in retinal vessel diameters was found (p < 0.01). Systemic oxygen saturation correlated negatively with perfusion density in the SVP and the DCP and retinal vessel diameters (p < 0.005 each). CONCLUSION: Our results show that systemic hyperoxia induces a significant decrease in vessel density in the DCP, while hypoxia leads to increased vessel density limited to the SVP. These results indicate that the retinal circulation shows the ability to adapt its blood flow to metabolic changes with high local resolution dependent on the capillary plexus.

Ultrawide field, distortion-corrected ocular shape estimation with MHz optical coherence tomography (OCT).

Ocular deformation may be associated with biomechanical alterations in the structures of the eye, especially the cornea and sclera in conditions such as keratoconus, congenital glaucoma, and pathological myopia. Here, we propose a method to estimate ocular shape using an ultra-wide field MHz swept-source optical coherence tomography (SS-OCT) with a Fourier Domain Mode-Locked (FDML) laser and distortion correction of the images. The ocular biometrics for distortion correction was collected by an IOLMaster 700, and localized Gaussian curvature was proposed to quantify the ocular curvature covering a field-of-view up to 65°×62°. We achieved repeatable curvature shape measurements (intraclass coefficient = 0.88 ± 0.06) and demonstrated its applicability in a pilot study with individuals (N = 11) with various degrees of myopia.

Developing a normative database for retinal perfusion using optical coherence tomography angiography.

Visualizing and characterizing microvascular abnormalities with optical coherence tomography angiography (OCTA) has deepened our understanding of ocular diseases, such as glaucoma, diabetic retinopathy, and age-related macular degeneration. Two types of microvascular defects can be detected by OCTA: focal decrease because of localized absence and collapse of retinal capillaries, which is referred to as the non-perfusion area in OCTA, and diffuse perfusion decrease usually detected by comparing with healthy case-control groups. Wider OCTA allows for insights into peripheral retinal vascularity, but the heterogeneous perfusion distribution from the macula, parapapillary area to periphery hurdles the quantitative assessment. A normative database for OCTA could estimate how much individual's data deviate from the normal range, and where the deviations locate. Here, we acquired OCTA images using a swept-source OCT system and a 12×12 mm protocol in healthy subjects. We automatically segmented the large blood vessels with U-Net, corrected for anatomical factors such as the relative position of fovea and disc, and segmented the capillaries by a moving window scheme. A total of 195 eyes were included and divided into 4 age groups: < 30 (n=24) years old, 30-49 (n=28) years old, 50-69 (n=109) years old and >69 (n=34) years old. This provides an age-dependent normative database for characterizing retinal perfusion abnormalities in 12×12 mm OCTA images. The usefulness of the normative database was tested on two pathological groups: one with diabetic retinopathy; the other with glaucoma.

Oxaliplatin and Gedatolisib (PKI-587) Co-Loaded Hollow Polydopamine Nano-Shells with Simultaneous Upstream and Downstream Action to Re-Sensitize Drugs-Resistant Hepatocellular Carcinoma to Chemotherapy.

Multidrug resistance (MDR) is a key to the ineffectiveness of hepatocellular carcinoma (HCC) chemotherapy. Oxaliplatin (OXA), as one of the first-line chemotherapeutic drugs for HCC, abnormally activates the PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR), causing drug resistance and consequnet compromised efficacy. Herein, we developed a hollow polydopamine nanoparticle (H-PDA)-based nano-delivery system (O/P-HP) that contained OXA and a dual PI3K/mTOR inhibitor PKI-587 with complementary effects for combating drug resistance in cancer chemotherapy. The hollow structure of H-PDA endowed O/P-HP with high loading efficiencies of OXA and PKI-587-up to 49.6% and 7.0%, respectively. In addition, benefiting from the intracellular delivery of H-PDA as well as the highly concentrated drugs therein, O/P-HP inhibited the proliferation of OXA-resistant HR cells, resulting in a cell viability of only 17.63%. These values were significantly superior to those with OXA single-agent treatment and treatment with free OXA in combination with PKI-587. We examined the intrinsic mechanisms of the combination therapy: O/PHP had excellent anti-cancer effects via the simultaneous upstream and downstream action to re-sensitize HR cells to chemotherapy; OXA induced strong apoptosis via the direct platinum lesions on DNA molecules, while PKI-587 normalized the abnormally activated PI3K/AKT/mTOR signaling pathway and DNA damage repair pathway (NHEJ and HR) that could attenuate the effectiveness of OXA, thus resulting in inhibition of cell proliferation, migration and DNA repair enzyme activity and the augment of apoptotic effects. Such combination therapy, with simultaneous upstream and downstream action, may be a strategy for minimizing resistance for anti-cancer treatments.

Seminal exosomal miR-210-3p as a potential marker of Sertoli cell damage in Varicocele.

BACKGROUND: Varicocoele-associated stressors, such as hypoxia and heat, can damage cell function and viability, and some exosomal biomarkers released from impaired cells may reflect the cell status in testis. OBJECTIVES: To find if seminal exosomal microRNAs can reflect the Sertoli cell function in varicocoele. MATERIALS AND METHODS: Experimental left varicocoele rat model was established (n = 24), and patients with different grades of varicocoele (n = 104) were enrolled. Primary rat Sertoli cells were isolated with enzymatic hydrolysis. Exosomes were isolated from primary rat Sertoli cells, rat epididymis tissue, and human seminal plasma with polymer-based precipitation method. Exosomal microRNAs were quantified with qPCR. Inhibin-B was detected with enzyme immunoassay. The correlation analysis between microRNA and inhibin-B was evaluated with Spearman's correlation. RESULTS: We screened 12 previously reported hypoxia-responsive microRNAs in the primary rat Sertoli cells and found that 4 exosomal microRNAs increased significantly in response to in vitro hypoxia treatment (P < .05). Of the 4 microRNAs, only miR-210-3p was upregulated in the rats with experimental varicocoele (P < .01). In the patients with varicocoele, we found that seminal exosomal miR-210-3p significantly increased in patients with grade II and III varicocoele (P < .01), and miR-210-3p negatively correlated with sperm count (P < .01) and seminal inhibin-B expression (r = -0.39, P < .01). For the 30 patients with microsurgical varicocelectomy, the operation notably decreased miR-210-3p (P < .01). DISCUSSION AND CONCLUSION: Seminal exosomal miR-210-3p may be a novel, sensitive, and non-invasive biomarker of Sertoli cell damage in varicocoele.

DUS4L Silencing Suppresses Cell Proliferation and Promotes Apoptosis in Human Lung Adenocarcinoma Cell Line A549.

PURPOSE: This study aims to investigate the potential role of DUS4L (dihydrouridine synthase 4 like) in lung adenocarcinoma (LUAD) and explore its associated pathways in human LUAD. METHODS: Firstly, we evaluated the relationships between clinicopathological characteristics and DUS4L expression via analysis of TCGA RNA sequencing data and other publicly available databases. Then, DUS4L was effectively silenced in LUAD cell line A549 using the lentiviral shRNA (short-hairpin RNA) transfection to assess its effects on cell proliferation, cycle and apoptosis in LUAD cells. RNA-seq technology was applied to shDUS4L and shCtrl-transfected cells to generate the corresponding gene expression profiles. Differentially expressed genes (DEGs) were identified using the DESeq2 program package. Also, DEGs were subjected to Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis to explore the associated molecular signaling pathways and relevant biological functions. RESULTS: Analysis of TCGA data revealed that DUS4L was highly upregulated in LUAD tissues which was related to clinical T and TNM stages of LUAD. The knockdown of DUS4L effectively inhibited cell proliferation and promoted apoptosis in A549 cells. Furthermore, the DEGs between the shDUS4L and shCtrl A549 cells were mainly enriched in biological processes associated with spliceosome, ribosome, RNA catabolic process, ncRNA (non-coding RNA) processing, and p53 signaling pathway. CONCLUSION: Altogether, our results suggest that DUS4L is significantly associated with tumorigenesis and could be utilized as a novel biomarker and therapeutic target for LUAD.

Prevalence and risk factors of postoperative delirium after spinal surgery: a meta-analysis.

OBJECTIVE: Postoperative delirium (POD) was common after spinal surgery, but the main findings in previous studies remained conflicting. This current meta-analysis was aimed at exploring the prevalence and risk factors of POD after spinal surgery. METHODS: PubMed and Embase were searched from inception to June 2019. Studies which reported the prevalence and risk factors of POD after spinal surgery were included. STATA version 12.0 was employed to analyze the pooled data. Statistical heterogeneity across included studies was identified using the I2 statistics. RESULTS: A total of 28 studies with 588,732 patients were included in the meta-analysis. The pooled prevalence of POD after spinal surgery was 0.85% (95%CI, 0.83-0.88%) with substantial heterogeneity (I2 = 97.3%). The central nervous system disorder (OR 4.73; 95%CI, 4.30-5.19) was a strong predictor for POD, whereas age (OR 1.16; 95%CI, 1.05-2.47; I2 = 99.2%) and blood loss (OR 1.10; 95%CI, 1.01-1.20; I2 = 93.3%) were weaker predictors. The funnel plot and statistical tests suggested that there existed potential publication bias, but the trim and fill method indicated that the pooled prevalence basically kept stable after adding two "missing" studies. CONCLUSIONS: The pooled POD after spinal surgery ranges from 0.83 to 0.88%. The central nervous system disorder, age, and blood loss were potential risk factors for POD.

Immune Infiltration Landscape in Clear Cell Renal Cell Carcinoma Implications.

The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor infiltrating immune cells (TIICs) recruited to the cancer microenvironment. Clear cell renal cell carcinoma (ccRCC) immune microenvironment plays an important role in the tumorigenesis. This research investigated the characteristics of immune cell invasion of renal cell carcinoma and provided clues for future clinical implementation. Retrospectively, ccRCC gene expression was analyzed with appropriate clinicopathological data from the Cancer Genome Atlas (TCGA) and GEO database up to December 2019. The CIBERSORT algorithm, meta-analysis, principal component analysis (PCA), Single-Sample Gene Set Enrichment Analysis (ssGSEA) and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. We also focused on evaluating the association with TIICs subpopulations and clinical features and molecular subtypes. TIICs subpopulation, especially Macrophages subgroup, T follicular helper (Tfh) cells and CD8 T cells, all contribute to tumorigenesis. Unsupervised clustering analysis revealed that there existed two distinct TIICs subgroups with different survival patterns. TIICs are extensively involved in the pathogenesis and development of the ccRCC. Characterizing the composition of TIICs influences the metabolism of tumors, activity, level, stage, and survival of patients. Collectively, the TIIC analysis has the potential to assist in the assessment and selection of ccRCC prognosis and treatment.