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Background Tumor necrosis factor receptor 2 (TNFR2) promotes tumor cell proliferation, activates immunosuppressive cells, and supports immune escape. However, its role in non‐small cell lung cancer (NSCLC) has not been reported. Methods Quantitative real‐time PCR and Western blotting were used to evaluate TNFR2 in three NSCLC cell lines (A549, H1299, H1975) and normal lung epithelial cells (BEAS‐2B). TNFR2 was evaluated in 71 tumor tissues and 25 adjacent normal lung tissues by immunohistochemistry and analyzed with respect to clinical parameters. Results The messenger RNA and protein levels of TNFR2 were significantly higher in A549, H1299, and H1975 cells than in BEAS‐2B cells (P

Abstract Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial‐to‐mesenchymal transition, reduces the production of pro‐fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254‐388aa interacts with Yes‐associated protein (YAP) at WW2 domain (231‐263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ‐Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4‐dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

Abstract Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1β, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

The effect of legume proteins (soy protein (SP), chickpea protein (CP) and peanut protein (PP)) on the properties of wheat starch-lauric acid (WS-LA) system and its intrinsic mechanism were investigated. RVA, digestion experiment and TGA results showed that legume proteins prompted the viscosity peak formation during cooling stage and increased anti-digestion and thermal stability of WS-LA system. FT-IR, Raman, XRD and 13C NMR results indicated that legume proteins improved the long-range and short-range ordering degree and single-helix structure of WS-LA system. SP had greater influence on the properties of WS-LA system than that of CP and PP. Proteins with high solubility, emulsifying properties and β-sheet content were conducive to starch-based complexes formation. Molecular dynamics simulation results indicated that major forces for WS-LA-SP formation were hydrogen bonding and van der Waals forces. This study offered crucial information on starch-fatty acid-protein complexes formation for proteins selection in starch-based products development.

Abstract Purpose Contrast‐enhanced spectral imaging (CEM) is a new mammography technique, but its diagnostic value in dense breasts is still inconclusive. We did a systematic review and meta‐analysis of studies evaluating the diagnostic performance of CEM for suspicious findings in dense breasts. Materials and Methods The PubMed, Embase, and Cochrane Library databases were searched systematically until August 6, 2023. Prospective and retrospective studies were included to evaluate the diagnostic performance of CEM for suspicious findings in dense breasts. The QUADAS‐2 tool was used to evaluate the quality and risk of bias of the included studies. STATA V.16.0 and Review Manager V.5.3 were used to meta‐analyze the included studies. Results A total of 10 studies (827 patients, 958 lesions) were included. These 10 studies reported the diagnostic performance of CEM for the workup of suspicious lesions in patients with dense breasts. The summary sensitivity and summary specificity were 0.95 (95% CI, 0.92–0.97) and 0.81 (95% CI, 0.70–0.89), respectively. Enhanced lesions, circumscribed margins, and malignancy were statistically correlated. The relative malignancy OR value of the enhanced lesions was 28.11 (95% CI, 6.84–115.48). The relative malignancy OR value of circumscribed margins was 0.17 (95% CI, 0.07–0.45). Conclusion CEM has high diagnostic performance in the workup of suspicious findings in dense breasts, and when lesions are enhanced and have irregular margins, they are often malignant.

The influenza virus neuraminidase has been well documented, yet the functions of mammalian neuraminidases remain less explored. Here, the authors show that neuraminidase 1 promotes renal fibrosis development by interacting with ALK5 to activate SMAD2/3.

Background: Gastric cancer (GC) stands as one of the most prevalent cancer types worldwide, holding the position of the second leading cause of cancer-related deaths. Gastric lesions represent pathological alterations to the gastric mucosa, with an elevated propensity to advance to gastric cancer. Limited research has explored the potential of stem cells in the treatment of gastric lesions. Methods: This study aimed to explore the potential of intravenous transplantation of labeled bone marrow-derived mesenchymal stem cells (BMMSCs) to inhibit the progression of precancerous gastric lesions. Results: In the gastric lesion disease model group, the rat tissue exhibited noteworthy mucosal atrophy, intestinal metaplasia, dysplasia, and inflammatory cell infiltration. Following the infusion of BMMSCs, a notable decrease in gastric lesions was found, with atrophic gastritis being the sole remaining lesion, which was confirmed by morphological and histological examinations. BMMSCs that were colonized at gastric lesions could differentiate into epithelial and stromal cells, as determined by the expression of pan-keratin or vimentin. The expression of vascular endothelial growth factor was significantly elevated following BMMSC transplantation. BMMSCs could also upregulate the production of humoral immune response cytokines, including interleukin (IL)-4 and IL-10, and downregulate the production of IL-17 and interferon-gamma, which could be highly associated with the cellular immune response and inflammation severity of the lesions. Conclusions: BMMSC transplantation significantly reduced inflammation and reversed gastric lesion progression.

Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our study provides an experimental basis for potential in vivo application of let-7a.

Abstract Background For patients with unresectable hepatocellular carcinoma (uHCC), intensity-modulated radiotherapy (IMRT) has become one of the options for clinical local treatment. Immune parameters, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and systemic immune inflammatory (SII), predict survival in various cancers. This study aimed to determine whether peripheral immune parameters can predict survival in patients with uHCC undergoing IMRT and establish a clinically useful prognostic nomogram for survival prediction. Methods The clinical data of 309 HCC patients were retrospectively analyzed and randomly divided into training (n = 216) and validation (n = 93) cohorts. PLR, NLR and SII were collected before and after IMRT. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors affecting survival, which were used to generate a nomogram. Results The median survival was 16.3 months, and significant increases in PLR, NLR, and SII were observed after IMRT (P

ObjectiveIn order to explore the relationship between mammographic density of breast mass and its surrounding area and benign or malignant breast, this paper proposes a deep learning model based on C2FTrans to diagnose the breast mass using mammographic density.MethodsThis retrospective study included patients who underwent mammographic and pathological examination. Two physicians manually depicted the lesion edges and used a computer to automatically extend and segment the peripheral areas of the lesion (0, 1, 3, and 5 mm, including the lesion). We then obtained the mammary glands’ density and the different regions of interest (ROI). A diagnostic model for breast mass lesions based on C2FTrans was constructed based on a 7: 3 ratio between the training and testing sets. Finally, receiver operating characteristic (ROC) curves were plotted. Model performance was assessed using the area under the ROC curve (AUC) with 95% confidence intervals (CI), sensitivity, and specificity.ResultsIn total, 401 lesions (158 benign and 243 malignant) were included in this study. The probability of breast cancer in women was positively correlated with age and mass density and negatively correlated with breast gland classification. The largest correlation was observed for age (r = 0.47). Among all models, the single mass ROI model had the highest specificity (91.8%) with an AUC = 0.823 and the perifocal 5mm ROI model had the highest sensitivity (86.9%) with an AUC = 0.855. In addition, by combining the cephalocaudal and mediolateral oblique views of the perifocal 5 mm ROI model, we obtained the highest AUC (AUC = 0.877 P < 0.001).ConclusionsDeep learning model of mammographic density can better distinguish benign and malignant mass-type lesions in digital mammography images and may become an auxiliary diagnostic tool for radiologists in the future.

Abstract Upregulation of lncRNA HOXA transcript at the distal tip (HOTTIP) plays important roles in cancer progression. Nevertheless, its functions in the growth and metastasis of ovarian carcinoma are unknown. In this study, we demonstrated overexpression of HOTTIP in ovarian cancer cell lines and clinical tissues. Further, we showed that higher level of HOTTIP was associated with poor survival of ovarian cancer patients. Notably, HOTTIP silencing restrained proliferation, migration, and invasiveness of ovarian carcinoma cells. On the other hand, upregulation of HOTTIP remarkably exacerbated the aggressive traits of ovarian carcinoma cells. In addition, HOTTIP served as a sponge of miR‐615‐3p to upregulate SMARCE1 level. Further, upregulation of miR‐615‐3p or downregulation of SMARCE1 reversed the carcinogenic impacts of HOTTIP in ovarian cancer. HOTTIP and miR‐615‐3p expression levels in ovarian cancer cells were negatively correlated, whereas HOTTIP and SMARCE1 expression levels were positively correlated. In nude mice, downregulation of HOTTIP reduced cell growth in vivo. In summary, lncRNA HOTTIP promotes the growth and metastatic phenotypes of ovarian cancer via regulating miR‐615‐3p/SMARCE1 pathway.

Abstract Parkinson’s disease is characterized by dopaminergic neuron loss and intracellular inclusions composed mainly of alpha synuclein (α-syn), but the mechanism of pathogenesis is still obscure. In recent years, more attention has been given to the gut as a key player in the initiation and progression of PD pathology. Several studies characterizing changes in the microbiome, particularly the gut microbiome, have been conducted. Although many studies found a decrease in the bacterial family Prevotellaceae and in butyrate-producing bacterial genera such as Roseburia and Faecalibacteria, and an increase in the genera Akkermansia many of the studies reported contradictory findings. In this review, we highlight the findings from the different studies and reflect on the future of microbiome studies in PD research.

Nickel (Ni) is ubiquitous in the environment and evidence has suggested that Ni can cause ocular surface inflammation, especially in fine particulate matter and personal products. Continuous daily exposure to Ni-containing dust may adversely impact the human cornea, whereas the underlying mechanism of this phenomenon remains not fully understood. Here, human corneal epithelial cells (HCEC) were employed to analyze the toxicity of Ni via detections of cell morphology, cell viability, reactive oxygen species production, cell apoptosis rate, and apoptotic gene expression levels after exposure for 24 h to uncover the damage of Ni to the cornea. A concentration-dependent inhibition of HCECs’ viability and growth was observed. In particular, Ni at 100 μM significantly decreased cell viability to 76%, and many cells displayed an abnormal shape and even induced oxidative damage of HCEC by increasing ROS to 1.2 times, and further led to higher apoptosis (24%), evidenced by up-regulation of apoptotic genes Caspase-8, Caspase-9, NF-κB, IL-1β, and Caspase-3, posing a risk of dry eye. Our study suggested that Ni induces apoptosis of HCEC through oxidative damage. Therefore, Ni pollution should be comprehensively considered in health risks or toxic effects on the ocular surface.

Breast cancer and osteoporosis are common diseases that affect the survival and quality of life in postmenopausal women. Women with breast cancer are more likely to develop osteoporosis than women without breast cancer due to certain factors that can affect both diseases simultaneously. For instance, estrogen and the receptor activator of nuclear factor-κB ligand (RANKL) play important roles in the occurrence and development of these two diseases. Moreover, chemotherapy and hormone therapy administered to breast cancer patients also increase the incidence of osteoporosis, and in recent years, neuropeptide Y (NPY) has also been found to impact breast cancer and osteoporosis.Y1 and Y5 receptors are highly expressed in breast cancer, and Y1 and Y2 receptors affect osteogenic response, thus potentially highlighting a potential new direction for treatment strategies. In this paper, the relationship between breast cancer and osteoporosis, the influence of NPY on both diseases, and the recent progress in the research and treatment of these diseases are reviewed.

Objective To determine the safety and effectiveness of a cross‐linked sodium hyaluronate (CHA) scaffold in cartilage repair. Methods Physicochemical properties of the scaffold were determined. The safety and effectiveness of the scaffold for cartilage repair were evaluated in a minipig model of a full‐thickness cartilage defect with microfracture surgery. Postoperative observation and hematological examination were used to evaluate the safety of the CHA scaffold implantation. Pathological examination as well as biomechanical testing, including Young's modulus, stress relaxation time, and creep time, were conducted at 6 and 12 months postsurgery to assess the effectiveness of the scaffold for cartilage repair. Furthermore, type II collagen and glycosaminoglycan content were determined to confirm the influence of the scaffold in the damaged cartilage tissue. Results The results showed that the routine hematological indexes of the experimental animals were within the normal physiological ranges, which confirmed the safety of CHA scaffold implantation. Based on macroscopic observation, it was evident that repair of the defective cartilage in the animal knee joint began during the 6 months postoperation and was gradually enhanced from the central to the surrounding region. The repair smoothness and color of the 12‐month cartilage samples from the operation area were better than those of the 6‐month samples, and the results for the CHA scaffold implantation group were better than the control group. Greater cell degeneration and degeneration of the adjacent cartilage was found in the implantation group compared with the control group at both 6 and 12 months postoperation, evaluated by O'Driscoll Articular Cartilage Histology Scoring. Implantation with the CHA scaffold matrix promoted cartilage repair and improved its compression capacity. The type II collagen level in the CHA scaffold implantation group tended to be higher than that in the control group at 6 months (2.33 ± 1.50 vs 1.68 ± 0.56) and 12 months postsurgery (3.37 ± 1.70 vs 2.06 ± 0.63). The GAG content in the cartilage of the control group was significantly lower than that of the experimental group (2.17 ± 0.43 vs 3.64 ± 1.17, P = 0.002 at 6 months and 2.27 ± 0.38 vs 4.12 ± 1.02, P = 0.002 at 12 months). Type II collagen and glycosaminoglycan content also demonstrated that CHA was beneficial for the accumulation of both these vital substances in the cartilage tissue. Conclusions The CHA scaffold displayed the ability to promote cartilage repair when applied in microfracture surgery, which makes it a promising material for application in the area of cartilage tissue engineering.

Abstract Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease. Methods In order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein (α-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse α-syn promoter. Results We observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner’s (submucosal) and Auerbach’s (myenteric) plexuses of the colon. Additionally, the phosphorylation of α-syn at serine 129 also increased with age and the aggregation of α-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, α-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin. Conclusions Our results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease caused by prion protein infection. Compared with other neurodegenerative diseases, neuronal cell apoptosis in CJD occurs more rapidly. It has become increasingly evident that sleep dysfunction is commonly seen in chronic neurodegenerative conditions and may present several years before the disease onset. Therefore, understanding the relation of dyssomnia to CJD may enhance our realization of the relationship between sleep disorders and other common neurodegenerative diseases. More and more studies have shown that sleep disorders are very common in CJD patients. Thus, clinicians should regularly screen for sleep conditions in possible CJD patients to enhance the diagnosis and treatment of CJD. DOI: 10.3969/j.issn.1672-6731.2018.04.011

Background/Aims: Non-invasive measurement of intracranial pressure (ICP) using ultrasound has garnered increasing attention. This study aimed to compare the reliability of ultrasonographic measurement of optic nerve sheath diameter (ONSD) and transcranial Doppler (TCD) in detecting potential ICP elevations.Methods: Patients who needed lumbar puncture (LP) in the Department of Neurology were recruited from December 2016 to July 2017. The ONSD and TCD measurements were completed before LP.Results: One hundred sixty-five participants (mean age, 41.96 ± 14.64 years; 80 men; 29 patients with elevated ICP) were included in this study. The mean ICP was 170 ± 52 mmH2O (range, 75–400 mmH2O). Univariate analyses revealed that ICP was non-significantly associated with TCD parameters and significantly associated with ONSD (r = 0.60, P < 0.001). The mean ONSD of the elevated ICP group was significantly higher than that of the normal ICP group (4.53 ± 0.40 mm vs. 3.97 ± 0.23 mm; P < 0.001). Multivariate linear regression determined that the difference between ICP and ONSD is significant.Conclusions: In the early stage of intracranial hypertension, ONSD is more reliable for evaluating ICP than TCD.

Parkinson’s disease (PD) is a neurodegenerative disease that is generally thought to be caused by multiple factors, including environmental and genetic factors. Emerging evidence suggests that intestinal disturbances, such as constipation, are common non-motor symptoms of PD. Gut inflammation may be closely associated with pathogenesis in PD. This review aims to discuss the cross-talk between gut inflammation and PD pathology initiation and progression. Firstly, we will highlight the studies demonstrating how gut inflammation is related to PD. Secondly, we will analyze how gut inflammation spreads from the gastro-intestine to the brain. Here, we will mainly discuss the neural pathway of pathologic α-syn and the systemic inflammatory routes. Thereafter, we will address how alterations in the brain subsequently lead to dopaminergic neuron degeneration, in which oxidative stress, glutamate excitotoxicity, T cell driven inflammation and cyclooxygenase-2 (COX-2) are involved. We conclude a model of PD triggered by gut inflammation, which provides a new angle to understand the mechanisms of the disease.

Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.

BACKGROUND: We have investigated the potential anticancer effects of karanjin, a principal furanoflavonol constituent of the Chinese medicine Fordia cauliflora, using cytotoxic assay, cell cycle arrest, and induction of apoptosis in three human cancer cell lines (A549, HepG2 and HL-60 cells). RESULTS: MTT cytotoxic assay showed that karanjin could inhibit the proliferation and viability of all three cancer cells. The induction of cell cycle arrest was observed via a PI (propidium iodide)/RNase Staining Buffer detection kit and analyzed by flow cytometry: karanjin could dose-dependently induce cell cycle arrest at G2/M phase in the three cell lines. Cell apoptosis was assessed by Annexin V-FITC/PI staining: all three cancer cells treated with karanjin exhibited significantly increased apoptotic rates, especially in the percentage of late apoptosis cells. CONCLUSION: Karanjin can induce cancer cell death through cell cycle arrest and enhance apoptosis. This compound may be effective clinically for cancer pharmacotherapy.

Background: Early detection, diagnosis, and treatment of children with CHD has been the focus of research attention. Hainan is the southernmost underdeveloped province in China, where the technology of screening, diagnosis, and treatment for children with CHD has not been fully developed. Objectives: This study aimed to introduce and promote an appropriate technology system for screening, diagnosis, and evaluation of neonatal CHD. Methods: Two indicators, namely cardiac auscultation plus pulse oximetry (POX), were used by screening staff to screen live newborns within six to 72 hours afterbirth at all screening institutions in Hainan province from January 1, 2019, to December 31,2021. Diagnosis procedure for the screened-positive newborns was performed in 31 certified medical institutions, and evaluation procedure for the newborns confirmed with CHD was performed in six certified medical institutions. Data about screening, diagnosis, evaluation, and treatment were obtained, uploaded, and managed online through a neonatal CHD screening information management net. Results: A total of 321447 live births were included in the CHD screening project, and an overall screening rate of 97.59% (321447/329387) was determined. According to our results, 8032 cases were screened-positive. A total of 1099 cases of CHD were confirmed, suggesting a CHD prevalence of 3.419 per 1000 live births. Atrial septal defect (ASD) was the most common CHD lesion, with a prevalence of 1.313 per 1000 live births. The sensitivity of cardiac auscultation, POX, and two indicators' combination (i.e., cardiac auscultation plus POX) for CHD detection were 69.15%, 33.49%, and 91.90%, respectively; and the specificity of them were 98.36%, 99.43%, and 97.81%, respectively. The ratio of both positive in two indicators among the children with major (serious and critical) CHD at the initial screening was significantly higher than that of single positive in any indicator (χ² = 59.455, P < 0.001). All children with CHD were evaluated, out of who 154 children with major CHD were treated promptly. Only 15 cases of children with major CHD died, and the standardized mortality of children aged 0-1 years with CHD was 4.67/100,000. Conclusions: It was concluded that the combination of two indicators (i.e., cardiac auscultation plus POX) for CHD screening was reliable as well as non-invasive, simple, and easy to operate so that it was conducive for promotion. It was also found that introducing and promoting an appropriate technology for screening, diagnosis, and evaluation of neonatal CHD were extremely significant since they may have contributed to the timely diagnosing and treating children with CHD, especially those with major CHD. [ABSTRACT FROM AUTHOR]

Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara-C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high-dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML.

The aim of this study was to investigate the antitumor activities of Phyllanthus amarus (PHA) and its potential of herb–drug interactions with 5-Fluorouracil (5-FU). Cell viability, ribonucleotides (RNs) and deoxyribonucleotides (dRNs) levels, cell cycle distribution, and expression of thymidylate synthase (TS) and ribonucleotide reductase (RR) proteins were measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method, flow cytometry and Western blot analysis, respectively. Our standardized PHA extract showed toxicity to HepG2 cells at high concentrations after 72 h exposure and induced G2/M cell cycle arrest. Combined use of 5-FU with PHA resulted in significant decreases in ATP, CTP, GTP, UTP and dTTP levels, while AMP, CMP, GMP and dUMP levels increased significantly compared with use of 5-FU alone. Further, PHA could increase the role of cell cycle arrest at S phase induced by 5-FU. Although PHA alone had no direct impact on TS and RR, PHA could change the levels of RNs and dRNs when combined with 5-FU. This may be due to cell cycle arrest or regulation of key enzyme steps in intracellular RNs and dRNs metabolism.

Background: Published studies have yielded inconsistent results on the relationship between p53 status and the progression of stage T1 non-muscle invasive bladder cancer (NMIBC). Therefore, we performed a meta-analysis to evaluate the prognostic value of p53 in T1 NMIBC. Methods: We systematically searched for relevant literatures in MEDLINE, EMBASE, and Web of Science. Data were pooled together from individual studies, and meta-analysis was performed. Study quality was assessed using the Newcastle-Ottawa Scale. Pooled risk ratios (RRs) and 95 % CI were calculated to estimate the effect sizes. Moreover, subgroup analyses were carried out. Results: A total of 12 studies comprising 712 patients were subjected to the final analysis. p53 overexpression was significantly associated with higher progression rate of T1 NMIBC (RR 2.32, 95 % CI 1.59-3.38). Moderate heterogeneity was observed across the studies (I2 = 39 %, P < 0.0001). In a subgroup analysis stratified by stage, p53 overexpression was a predictor of progression in T1 grade 3 NMIBC (RR 2.71, 95 % CI 1.31-5.64). In addition, in a subgroup analysis stratified by intravesical therapy, p53 overexpression was a predictor of progression in T1 NMIBC received Bacillus Calmette-Guérin intravesical therapy (RR 3.35, 95 % CI 1.89-5.93). Furthermore, after excluding the study that possibly contributed to the heterogeneity by the sensitivity analysis, the association p53 overexpression was significantly correlated with progression of T1 NMIBC (RR 2.74, 95 % CI 2.05-3.65) without evidence of heterogeneity (I2 = 0 %, P < 0.0001). Conclusions: This meta-analysis suggested that p53 overexpression may be associated with progression of T1 NMIBC patients. Because of the heterogeneity and other limitations, further studies with rigid criteria and large populations are still warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

PerforalactoneA (1), a new 20S quassinoid with a unique cagelike 2,4-dioxaadamantane ring system and a migrated side chain, was isolated from the plant Harrisonia perforata together with two biosynthetically related new quassinoids. The structures of these natural products were elucidated by NMR spectroscopy, X-ray diffraction analysis, computational modeling, and the CD excitation chirality method. The compounds exhibited notable biological properties, including insecticidal activity against Aphis medicaginis Koch and antagonist activity at the nicotinic acetylcholine receptor of Drosophila melanogaster. The structural features of these compounds may be related to their promising biological characteristics. Their biosynthesis and an alternative origin of quassinoid-type natural products are also discussed. [ABSTRACT FROM AUTHOR]

Crohn's Disease (CD) is a chronic immune-mediated disorder with progressive and destructive course. Current guidelines on the treatment strategy still recommend a step-up approach with sequential prescription of corticosteroids and immunosuppressives. However, mounting evidences manifested that top-down therapy with early administration of anti-TNF or combination of immunosuppressives can achieve more rapid and higher rate of mucosal healing and has the potential of modifying the natural course of disease. Therefore, who is suitable to accept and when to start anti-TNF therapy have attracted the attention of gastroenterologists. And what benefit/risk can be expected from the two strategies should be carefully taken into account by clinicians. Age stratification, special patients, disease location and extension, genetic and serologic testing are predictors of disease progression and complication and thus guide a personalized treatment approach in CD. A definition of early CD has been proposed to select an algorithm for treatment of moderate-to-severe CD with a suitable strategy. To date mucosal healing has been widely used, the Lémann score, which assesses the extent and severity of bowel damage at a specific time-point and over time, and is a new disability index for patients with CD, will be considered as a new endpoint for future studies of treatment strategies. Besides medicines of the two strategies, surgery, vaccine, Leukocytapheresis and stem cell therapy are all effective therapeutic approaches which lead to another thinking about what should they be putted in the conditional pyramid. However, we are trying to answer these questions. [ABSTRACT FROM AUTHOR]

We report a prebiotically relevant solution to the N1-ribosylation of pyrimidine nucleobases, a well-known challenge to the RNA world hypothesis. We found that the presence of metal cations and clay minerals enable the previously unachievable direct ribosylation of uracil. Spectroscopy and chromatography analyses confirmed the formation of ribosylated uracil. The method can be extended to the ribosylation of 2-pyrimidinone. These findings are also compatible with the metal-doped-clay model, developed by our lab for the unified route of the selection of ribose and subsequent syntheses of nucleotide and RNA.