ABSTRACT
PURPOSE: To compare clinical outcomes of high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) for anterior medial osteoarthritis (AMOA) as well as offer surgical recommendations through age stratification. METHODS: Between May 2019 and May 2021, 68 cross-indicated AMOA patients were analyzed. The patients were divided into HTO and UKA groups and further into two age groups of 55-60 and 60-65 years. Additionally, general data, visual analog scale (VAS) score, and Hospital for Special Surgery knee score (HSS) were analyzed. RESULTS: All the patients were followed up for 18 months. Knee joint HSS significantly improved, and VAS score decreased in both groups (P < 0.05). In the 55-60 age group, HTO showed superior knee HSS at 1 and 3 months (P < 0.05), with no significant difference at 6, 12, and 18 months. HTO had a significantly lower VAS score at one month, and the VAS scores of the two groups decreased gradually with no significant difference. In the 60-65 age group, the UKA group showed superior knee joint HSS at one month, with no significant difference at 3, 6, 12, and 18 months. The UKA group had a significantly lower VAS score at one month, and both groups' VAS scores decreased gradually with no significant difference. CONCLUSION: Both methods yield satisfactory results for AMOA cross-indications, improving knee joint function. The observed recovery trends have implications for personalized surgical recommendations, guiding interventions based on age-specific considerations for optimal outcomes in anterior medial osteoarthritis cases.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Osteotomy , Humans , Osteoarthritis, Knee/surgery , Middle Aged , Female , Male , Aged , Age Factors , Arthroplasty, Replacement, Knee/methods , Osteotomy/methods , Tibia/surgery , Treatment Outcome , Pain Measurement , Visual Analog ScaleABSTRACT
BACKGROUND: Understanding the trends of tuberculosis (TB) burden and its risk factors at the provincial level in the context of global End TB targets is crucial to identify the progress and challenges in TB control. We aimed to estimate the burden of TB and risk factors for death from 2006 to 2020 for the first time in Guizhou Province, China. METHODS: Data were collected from the national TB surveillance system. Four indicators of TB burden and their corresponding age-standardized rates (ASRs), including incidence (ASIR), prevalence (ASPR), mortality (ASMR) and disability-adjusted life years (DALYs) (ASDR), were estimated and stratified by year, age, gender and prefecture. Temporal trends of ASRs were presented by locally weighted regression, and the annual percentage change was calculated. The correlation between gross domestic product (GDP) per capita and ASRs was evaluated by Pearson correlation analysis. The associated risk factors for death in PTB patients were determined using logistic regression models. RESULTS: A total of 557,476 pulmonary TB (PTB) cases and 11,234 deaths were reported, including 2233 (19.9%) TB specific deaths and 9001 (80.1%) deaths from other causes. The 15-year average incidence, prevalence and mortality rates were 94.6, 102.6 and 2.1 per 100,000 population, respectively. The average DALY rate was 0.60 per 1000 population. The ASIR and ASPR have shown downward trends since 2012, with the largest percentage decrease in 2020 (ASIR: -29.8%; ASPR: -30.5%). The number in TB specific deaths consistently decreased during the study period (P<0.001), while the increase in deaths from other causes drove the overall upward trend in ASMR and ASDR. Four ASRs remained high in males and 5 prefectures. GDP per capita was negatively associated with the ASIR, ASPR and ASDR (P<0.05). Among PTB patients, men, patients with no fixed job, those with a low GDP level, patients with increasing age, those previously treated, those with severe symptoms, those transferred in and those receiving directly observed treatment were more likely to suffer death. CONCLUSION: Guizhou has made progress in reducing PTB cases and TB specific deaths over the last 15 years. Targeted interventions are needed to address these risk factors for death in PTB patients and high-risk areas.
Subject(s)
Tuberculosis, Pulmonary , Tuberculosis , Male , Humans , Risk Factors , Tuberculosis/epidemiology , Tuberculosis, Pulmonary/epidemiology , China/epidemiology , Disability-Adjusted Life Years , Quality-Adjusted Life Years , Global Burden of Disease , Incidence , Global HealthABSTRACT
PURPOSE: To analyze the clinical effects of different positions of the weight-bearing axis (WBA) after high tibial osteotomy (HTO). METHODS: The clinical data of 90 patients who underwent HTO in the Department of Orthopedics at our hospital from June 2018 to June 2021 were retrospectively analyzed. Patients were divided into groups A and B (n = 45 per group) according to different post-HTO WBA positions of the affected side. WBAs in both groups were at 50-60% and 62-66% of the tibial plateau, from inside to outside, respectively. American Hospital for Special Surgery Knee Score (HSS), visual analog scale (VAS) score, femorotibial angle (FTA), and medial proximal tibial angle (MPTA) were recorded and analyzed. RESULTS: All patients were followed up with for 12 months. HSS scores increased gradually and VAS scores decreased gradually in both groups preoperatively, and at 3 months, 6 months, and 1 year postoperatively (P < 0.05). Compared to group A, group B had better HHS scores at 6 months and 1 year postoperatively (P < 0.05). There was no significant between-group difference in VAS scores at all aforementioned timepoints (P > 0.05). Postoperative MPTA and FTA were 89.56° ± 2.18° and 177.11° ± 2.63° in group A, and 89.07° ± 1.98° and 177.07° ± 2.36° in group B, respectively, with no significant between-group difference (P > 0.05). CONCLUSION: Patients with post-HTO WBA ranges of 50-60% and 62-66% achieved knee joint function improvement and pain relief. Half a year later, those with a WBA range of 62-66% had better knee joint function scores. However, a comparison of long-term effects warrants further investigation.
Subject(s)
Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/surgery , Knee Joint/surgery , Retrospective Studies , Tibia/surgery , Osteotomy , Weight-BearingABSTRACT
BACKGROUND: Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease. METHODS: A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis. FINDINGS: High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis. INTERPRETATION: We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis. FUNDING: This work was supported by National Key Research and Development Program of China (2021YFC2501000, 2021YFC2501900, 2017YFA0505100); National Natural Science Foundation of China (31961160727, 82073196, 81973339, 81803551); NSFC/RGC Joint Research Scheme (N_HKU727/19); Natural Science Foundation of Guangdong Province (2021A1515011158, 2021A0505030035); Key Laboratory of Guangdong Higher Education Institutes of China (2021KSYS009).
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , MicroRNAs , Humans , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Neoplasms/genetics , Molecular Docking Simulation , CRISPR-Cas Systems , Early Detection of Cancer , MicroRNAs/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Proliferation , Cell Movement/genetics , DNA-Binding Proteins/genetics , Transcription Factors/geneticsABSTRACT
Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.
Subject(s)
Lysine , Neoplasms , Humans , Lysine/metabolism , Epigenesis, Genetic , Acylation , Protein Processing, Post-Translational , Acetyltransferases/metabolism , Neoplasms/genetics , N-Terminal Acetyltransferases/genetics , N-Terminal Acetyltransferases/metabolism , Ubiquitin-Specific Proteases/geneticsABSTRACT
Colorectal cancer (CRC) is one of the most common malignant tumors in the world, with high prevalence and low 5-year survival. Most of the CRC patients show excessive activation of the Wnt/ß-catenin pathway which is a vital target for CRC treatment. Based on multiple CRC cell lines with different nuclear expression of ß-catenin, NU2058 is identified from a small molecule library consisting of 280 bioactive compounds and found to selectively inhibit the proliferation of CRC cells with nuclear ß-catenin activation in vitro and in vivo. The translational significance of NU2058 alone or in combination with chemotherapeutic drugs oxaliplatin and irinotecan (SN38) in CRC is demonstrated in orthotopic tumor model and patient-derived xenograft models. By integrating limited proteolysis-small molecule mapping (LiP-SMap) and mass spectrometry (MS), Ran-binding protein 3 (RanBP3) is identified as the direct target of NU2058. The results show that RanBP3 is a tumor suppressor in CRC and is associated with patient survival. Mechanistically, NU2058 increases the interaction of RanBP3 and ß-catenin to promote nuclear export of ß-catenin, which further inhibits transcription of c-Myc and cyclin D1 to induce cell senescence. Collectively, NU2058 may serve as a promising therapeutic agent for CRC patients with selective disruption of pathologic Wnt/ß-catenin signaling.
Subject(s)
Cellular Senescence , Colorectal Neoplasms , Nuclear Proteins , Nucleocytoplasmic Transport Proteins , beta Catenin , Humans , Animals , Carcinogenesis , Wnt Signaling PathwayABSTRACT
As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.
ABSTRACT
N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into the regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3, whereas SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration-approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC. SIGNIFICANCE: This study finds that METTL3 promotes cancer metastasis by activating EGR1/Snail signaling in an m6A-dependent manner, revealing vulnerability to METTL3 blockade in esophageal squamous cell carcinoma.
Subject(s)
Anti-HIV Agents , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Adenosine/metabolism , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Humans , Methyltransferases/genetics , Methyltransferases/metabolism , Molecular Docking Simulation , Pharmaceutical Preparations , Quinolones , RNA, Messenger/genetics , Ubiquitin-Protein LigasesABSTRACT
With the development of proteomics and epigenetics, a large number of RNA-binding proteins (RBPs) have been discovered in recent years, and the interaction between long non-coding RNAs (lncRNAs) and RBPs has also received increasing attention. It is extremely important to conduct in-depth research on the lncRNA-RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA-RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6-methyladenosine (m6A) modification of lncRNAs. In addition, we discussed how the lncRNA-RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA-RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.
Subject(s)
Neoplasms , RNA, Long Noncoding , Epigenesis, Genetic , Humans , Neoplasms/genetics , Neoplasms/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Insecure applications (apps) are increasingly used to steal users' location information for illegal purposes, which has aroused great concern in recent years. Although the existing methods, i.e., static and dynamic taint analysis, have shown great merit for identifying such apps, which mainly rely on statically analyzing source code or dynamically monitoring the location data flow, identification accuracy is still under research, since the analysis results contain a certain false positive or true negative rate. In order to improve the accuracy and reduce the misjudging rate in the process of vetting suspicious apps, this paper proposes SAMLDroid, a combined method of static code analysis and machine learning for identifying Android apps with location privacy leakage, which can effectively improve the identification rate compared with existing methods. SAMLDroid first uses static analysis to scrutinize source code to investigate apps with location acquiring intentions. Then it exploits a well-trained classifier and integrates an app's multiple features to dynamically analyze the pattern and deliver the final verdict about the app's property. Finally, it is proved by conducting experiments, that the accuracy rate of SAMLDroid is up to 98.4%, which is nearly 20% higher than Apparecium.
ABSTRACT
Colorectal cancer (CRC) is one of the most common malignancies worldwide, and effective therapy remains a challenge. In this study, we take advantage of a drug repurposing strategy to screen small molecules with novel anticancer activities in a small-molecule library consisting of 1056 FDA-approved drugs. We show, for the first time, that lomitapide, a lipid-lowering agent, exhibits antitumor properties in vitro and in vivo. Activated autophagy is characterized as a key biological process in lomitapide-induced CRC repression. Mechanistically, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. Autophagy inhibition or AMPK silencing significantly abrogated lomitapide-induced cell death, indicating the significance of AMPK-regulated autophagy in the antitumor activities of lomitapide. More importantly, PP2A was identified as a direct target of lomitapide by limited proteolysis-mass spectrometry (LiP-SMap), and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Taken together, the results of the study reveal that lomitapide can be repositioned as a potential therapeutic drug for CRC treatment.
ABSTRACT
This study aimed to screen novel anticancer strategies from FDA-approved non-cancer drugs and identify potential biomarkers and therapeutic targets for colorectal cancer (CRC). Methods: A library consisting of 1056 FDA-approved drugs was screened for anticancer agents. WST-1, colony-formation, flow cytometry, and tumor xenograft assays were used to determine the anticancer effect of azelastine. Quantitative proteomics, confocal imaging, Western blotting and JC-1 assays were performed to examine the effects on mitochondrial pathways. The target protein of azelastine was analyzed and confirmed by DARTS, WST-1, Biacore and tumor xenograft assays. Immunohistochemistry, gain- and loss-of-function experiments, WST-1, colony-formation, immunoprecipitation, and tumor xenograft assays were used to examine the functional and clinical significance of ARF1 in colon tumorigenesis. Results: Azelastine, a current anti-allergic drug, was found to exert a significant inhibitory effect on CRC cell proliferation in vitro and in vivo, but not on ARF1-deficient or ARF1-T48S mutant cells. ARF1 was identified as a direct target of azelastine. High ARF1 expression was associated with advanced stages and poor survival of CRC. ARF1 promoted colon tumorigenesis through its interaction with IQGAP1 and subsequent activation of ERK signaling and mitochondrial fission by enhancing the interaction of IQGAP1 with MEK and ERK. Mechanistically, azelastine bound to Thr-48 in ARF1 and repressed its activity, decreasing Drp1 phosphorylation. This, in turn, inhibited mitochondrial fission and suppressed colon tumorigenesis by blocking IQGAP1-ERK signaling. Conclusions: This study provides the first evidence that azelastine may be novel therapeutics for CRC treatment. ARF1 promotes colon tumorigenesis, representing a promising biomarker and therapeutic target in CRC.
Subject(s)
ADP-Ribosylation Factor 1/metabolism , Colonic Neoplasms/drug therapy , Dynamins/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Mitochondrial Dynamics/drug effects , Phthalazines/pharmacology , ras GTPase-Activating Proteins/metabolism , ADP-Ribosylation Factor 1/genetics , Animals , Anti-Allergic Agents/pharmacology , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dynamins/genetics , Extracellular Signal-Regulated MAP Kinases/genetics , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Prognosis , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , ras GTPase-Activating Proteins/geneticsABSTRACT
Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFß2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGFß2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGFß2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGFß2 promoter, represses TGFß2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGFß2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis.
ABSTRACT
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.
Subject(s)
Biological Products/therapeutic use , Chalcones/therapeutic use , Esophageal Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Apoptosis , Autophagy , Biological Products/pharmacology , Cell Line, Tumor , Cell Proliferation , Chalcones/pharmacology , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Signal Transduction , TransfectionABSTRACT
BACKGROUND: A suitable fundus camera for telemedicine screening can expand the scale of eye care service. The purpose of this study was to compare a handheld nonmydriatic digital fundus camera and a conventional mydriatic fundus camera according to the image quality of their photographs and usability of those photographs to accurately diagnose various retinal diseases. METHODS: A handheld nonmydriatic fundus camera and conventional fundus camera were used to take fundus photographs of outpatients at an ophthalmic clinic before and after pupillary dilation. Image quality and diagnostic agreement of the photos were graded by two masked and experienced retinal specialists. RESULTS: A total of 867 photographs of 393 eyes of 200 patients were collected. Approximately 80% of photos taken under nonmydriasis status using the handheld nonmydriatic fundus camera had good (55.7%) or excellent (22.7%) image quality. The overall agreement of diagnoses between the doctors was more than 90%. When the handheld nonmydriatic fundus camera was used after mydriasis, the proportion of images with good (45%) or excellent (49.7%) quality reached 94.7% and diagnostic agreement was 93.4%. Lens opacity was associated with the quality of images obtained using the handheld camera (p = 0.041), and diagnosis disagreement for handheld camera images was associated with preexisting diabetes diagnosis (p = 0.009). Approximately 40% of patients expressed preference for use of the handheld nonmydriatic camera. CONCLUSION: This study demonstrated the effectiveness of the handheld nonmydriatic fundus camera in clinical practice and its feasibility for telemedicine screening of retinal diseases.
Subject(s)
Diagnostic Techniques, Ophthalmological/instrumentation , Photography/instrumentation , Retinal Diseases/diagnosis , Telemedicine/methods , Adult , Aged , Feasibility Studies , Female , Fundus Oculi , Humans , Male , Middle AgedABSTRACT
Vascular endothelial dysfunction is the major contributing factor to hypertension. Endothelial progenitor cells (EPCs) are essential for endogenous vascular endothelial renovation. The activity and number of circulating EPCs are preserved in prehypertensive premenopausal females according to our previous research. However, the changes of EPCs in prehypertensive postmenopausal females are poorly understood, and the mechanisms responsible for the loss of the gender protection advantage of cardiovascular disease remain unexplored. In order to determine the effects of EPCs in prehypertensive postmenopausal females, the number and activity of circulating EPCs were tested in the present study. Next, the function of EPCs secreting nitric oxide (NO), vascular endothelial growth factor (VEGF) and granulocytemacrophage colonystimulating factor (GMCSF), as well as their concentration in the plasma, were measured. The association between flowmediated dilation (FMD) and EPC secretion was also assessed. Attenuation of proliferation and migration of EPCs was observed in prehypertensive patients in comparison with normotensive subjects. In addition, a reduced NO production secreted by EPCs was detected in prehypertensive patients as compared with that in normotensive patients. There was no significant difference in EPC function between postmenopausal females and agematched males. Finally, the association between FMD and NO production was validated. Collectively, these data indicated that impaired EPCs mediated vasodilation dysfunction via decreasing NO production. Therefore, EPC function enhancement and NO level augmentation are emerging as novel therapeutic strategies for prehypertension therapy.
Subject(s)
Endothelial Progenitor Cells/pathology , Hypertension/etiology , Hypertension/physiopathology , Nitric Oxide/metabolism , Postmenopause , Vasodilation , Blood Pressure , Cell Movement , Cell Proliferation , Cells, Cultured , Endothelial Progenitor Cells/metabolism , Female , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Hypertension/blood , Hypertension/metabolism , Male , Middle Aged , Nitric Oxide/blood , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Collateralization is an important way for patients with coronary heart disease to supply blood flow to the ischemic area. At present, research on the mechanism of collateral circulation mainly focuses on the inflammatory response. Monocytes are the kernel of inflammatory response during arteriogenesis. Therefore, we reviewed the recent developments in this field in terms of the dynamic changes of monocytes during collateralization. We searched and scanned PubMed for the following terms until November 2018: collateral, collateralization, monocyte, macrophage, and arteriogenesis. Articles were obtained and examined to figure out the dynamics of monocytes in the progress of collateralization. Substantial research shows that recruitment, infiltration, and phenotypic transformation of monocytes can affect function in various ways, respectively. Mechanical or chemical factors that can produce effects on collateral development may be due partly to impact on dynamics of monocytes. Although mechanisms of dynamics of monocytes during arteriogenesis are not elucidated clearly, there is no doubt that deeper exploration of the underlying mechanisms will contribute to pharmaceutical development aiming for promoting collateral development.
ABSTRACT
Xanthine oxidase (XO) is one of the major enzymes to generate superoxide anion (O2(-)), that is frequently associated with various diseases involving reactive oxygen species (ROS). 4-Amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor showing therapeutic potential for oxidative inflammatory diseases. However its very poor aqueous solubility makes pharmaceutical application difficult. To overcome this drawback, we have successfully synthesized a water soluble polyethylene glycol (PEG) conjugate of AHPP (PEG-AHPP) that exhibited good water solubility, forming micelles in aqueous solution. In the present study, the in vivo pharmacokinetics of this PEG-AHPP was examined. Further its therapeutic potential was investigated in dextran sulfate sodium (DSS) induced mouse colitis model. Compared to parental AHPP, the plasma t1/2 of PEG-AHPP was increased remarkably from 3h to 14h, indicating macromolecular nature of AHPP in circulation. In the DSS induced colitis model, oral administration of 2% DSS in drinking water resulted in the progression of the colitis with diarrhea and hematochezia as well as shortening of the large bowel. Administration of PEG-AHPP intravenously (10mg/kg) or orally (20mg/kg) suppressed pathogenesis significantly; namely diarrhea was reduced markedly, and the length of large bowel returned to almost normal level. Pathological examination clearly revealed improvement of colonic ulcer or necrosis. Production of inflammatory cytokines, i.e., interleukin-6 and tumor necrosis factor (TNF)-α, was significantly increased in DSS-induced colitis mice. However, it was markedly suppressed by PEG-AHPP administration. Similar results were found when serum 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances (TBARS), that are the index of oxidative injury, were measured. PEG-AHPP thus may be a potential candidate drug for ROS-related diseases including inflammatory bowel disease.
Subject(s)
Colitis/drug therapy , Oxypurinol/analogs & derivatives , Polyethylene Glycols/administration & dosage , Xanthine Oxidase/antagonists & inhibitors , 8-Hydroxy-2'-Deoxyguanosine , Animals , Caco-2 Cells , Colitis/chemically induced , Colitis/immunology , Colitis/metabolism , Colon/drug effects , Colon/immunology , Colon/metabolism , Colon/pathology , Cytokines/immunology , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/blood , Dextran Sulfate , Female , Humans , Mice, Inbred ICR , Micelles , Oxypurinol/administration & dosage , Oxypurinol/pharmacokinetics , Oxypurinol/therapeutic use , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/therapeutic use , Reactive Oxygen Species , Solubility , Thiobarbituric Acid Reactive Substances/analysis , Water/chemistry , Xanthine Oxidase/blood , Xanthine Oxidase/metabolismABSTRACT
Previous studies indicated the potential of zinc protoporphyrin (ZnPP) as an antitumor agent targeting to the tumor survival factor heme oxygenase-1, and/or for photodynamic therapy (PDT). In this study, to achieve tumor-targeted delivery, styrene-maleic acid-copolymer conjugated ZnPP (SMA-ZnPP) was synthesized via amide bond, which showed good water solubility, having ZnPP loading of 15%. More importantly, it forms micelles in aqueous solution with a mean particle size of 111.6 nm, whereas it has an apparent Mw of 65 kDa. This micelle formation was not detracted by serum albumin, suggesting it is stable in circulation. Further SMA-ZnPP conjugate will behave as an albumin complex in blood with much larger size (235 kDa) by virtue of the albumin binding property of SMA. Consequently, SMA-ZnPP conjugate exhibited prolonged circulating retention and preferential tumor accumulation by taking advantage of enhanced permeability and retention (EPR) effect. Clear tumor imaging was thus achieved by detecting the fluorescence of ZnPP. In addition, the cytotoxicity and PDT effect of SMA-ZnPP conjugate was confirmed in human cervical cancer HeLa cells. Light irradiation remarkably increased the cytotoxicity (IC50, from 33 to 5 µM). These findings may provide new options and knowledge for developing ZnPP based anticancer theranostic drugs.