Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer.

Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

Serum levels of PDGF-CC as a potential biomarker for the diagnosis of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that predominantly affects children, and no specific diagnostic biomarkers for KD are available. Platelet-derived growth factor CC (PDGF-CC) is a peptide with angiogenic properties that has been amply demonstrated to play a critical role in the cardiovascular system. This study aimed to investigate the serum expression of PDGF-CC in children with KD and to evaluate the ability of PDGF-CC to diagnose KD. METHODS: A total of 96 subjects, including 59 KD patients, 17 febrile controls (FC), and 20 healthy controls (HC), were enrolled. Serum levels of PDGF-CC were measured via enzyme-linked immunosorbent assay. The associations between PDGF-CC and clinical laboratory parameters were investigated by correlation analysis. The diagnostic performance was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Serum PDGF-CC levels in the KD group were significantly higher than in the FC and HC groups. Serum PDGF-CC levels in the KD group were positively correlated with white blood cell counts, percentage of neutrophils, IL-2, IL-12p70, TNF-α, and IL-1ß levels, and negatively correlated with the percentage of lymphocytes. In the analysis of ROC curves, the area under the curve was 0.796 (95% confidence interval 0.688-0.880; P < 0.0001) for PDGF-CC and increased to 0.900 (95% confidence interval 0.808-0.957; P < 0.0001) in combination with white blood cell counts and C-reactive protein. CONCLUSIONS: PDGF-CC is a potential biomarker for KD diagnosis, and the combination with white blood cell counts and C-reactive protein can further improve diagnostic performance.

Proapoptotic effect of WS-299 induced by NOXA accumulation and NRF2-counterbalanced oxidative stress damage through targeting RBX1-UBE2M interaction in gastric cancers.

The abnormal activation of Cullin RING E3 Ligases (CRLs) is closely associated with the occurrence and development of various cancers. Targeting the neddylation pathway represents an effective approach for cancer treatment. In this work, we reported that WS-299, structurally featuring a coumarin moiety attached to the triazolopyrimidine, exhibited excellent anti-proliferative activity in MGC-803 and HGC-27 cells. WS-299 exerted potent anticancer effects by inhibiting clone formation, EdU incorporation and inducing cell cycle arrest. WS-299 inhibited CUL3/5 neddylation and caused an obvious accumulation of Nrf2 and NOXA, substrates of CRL3 and CRL5, respectively. Biochemical studies showed that WS-299 inhibited CUL3 neddylation by inhibiting RBX1-UBE2M interaction. The anti-proliferative effect of WS-299 was mainly induced by NOXA-mediated apoptosis. Of note, Nrf2 attenuated WS-299-induced reactive oxygen species (ROS) levels. Furthermore, Nrf2 accumulation also had an antagonistic effect on NOXA-induced apoptosis. Therefore, WS-299 and siNrf2 synergistically increased ROS levels, apoptotic cells and suppressed tumor growth in vivo. Taken together, our research clarified the anti-cancer mechanisms of WS-299 through targeting the RBX1-UBE2M protein-protein interaction and inhibiting the neddylation modification of CUL3 and CUL5. More importantly, our studies also demonstrated that combination of WS-299 with shNrf2 could be an effective strategy for treating gastric cancers.

Prediction of Coronary Artery Lesions in Patients With Recurrent Kawasaki Disease.

BACKGROUND: A subset of patients with Kawasaki disease (KD) will suffer recurrence. However, there is still a lack of accurate prediction models for coronary artery lesions (CAL) in recurrent KD patients. It is necessary to establish a new nomogram model for predicting CAL in patients with recurrent KD. METHODS: Data from patients with recurrent KD between 2015 and 2021 were retrospectively reviewed. After splitting the patients into training and validation cohorts, the least absolute shrinkage and selection operator was used to select the predictors of CAL and multivariate logistic regression was used to construct a nomogram based on the selected predictors. The application of area under the receiver operating characteristic curve (AUC), calibration curves, Hosmer-Lemeshow test, Brier score and decision curve analysis were used to assess the model performance. RESULTS: A total of 159 recurrent KD patients were enrolled, 66 (41.5%) of whom had CAL. Hemoglobin levels, CAL at the first episode, and intravenous immunoglobulin resistance at recurrence were identified by the least absolute shrinkage and selection operator regression analysis as significant predictors. The model incorporating these predictors showed good discrimination (AUC, 0.777) and calibration capacities (Hosmer-Lemeshow P value, 0.418; Brier score, 0.190) in the training cohort. Application of the model to the validation cohort yielded an AUC of 0.741, a Hosmer-Lemeshow P value of 0.623 and a Brier score of 0.190. The decision curve analysis demonstrated that the nomogram model was clinically useful. CONCLUSIONS: The proposed nomogram model could help clinicians assess the risk of CAL in patients with recurrent KD.

Characterization and commissioning of a new collaborative multi-modality radiotherapy platform.

TaiChi, a new multi-modality radiotherapy platform that integrates a linear accelerator, a focusing gamma system, and a kV imaging system within an enclosed O-ring gantry, was introduced into clinical application. This work aims to assess the technological characteristics and commissioning results of the TaiChi platform. The acceptance testing and commissioning were performed following the manufacturer's customer acceptance tests (CAT) and several AAPM Task Group (TG) reports/guidelines. Regarding the linear accelerator (linac), all applicable validation measurements recommended by the MPPG 5.a (basic photon beam model validation, intensity-modulated radiotherapy (IMRT)/volumetric-modulated arc therapy (VMAT) validation, end-to-end(E2E) tests, and patient-specific quality assurance (QA)) were performed. For the focusing gamma system, the absorbed doses were measured using a PTW31014 ion chamber (IC) and PTW60016 diode detector. EBT3 films and a PTW60016 diode detector were employed to measure the relative output factors (ROFs). The E2E tests were performed using PTW31014 IC and EBT3 films. The coincidences between the imaging isocenter and the linac/gamma mechanical isocenter were investigated using EBT3 films. The image quality was evaluated regarding the contrast-to-noise ratio (CNR), spatial resolution, and uniformity. All tests included in the CAT met the manufacturer's specifications. All MPPG 5.a measurements complied with the tolerances. The confidence limits for IMRT/VMAT point dose and dose distribution measurements were achieved according to TG-119. The point dose differences were below 1.68% and gamma passing rates (3%/2 mm) were above 95.1% for the linac E2E tests. All plans of patient-specific QA had point dose differences below 1.79% and gamma passing rates above 96.1% using the 3%/2 mm criterion suggested by TG-218. For the focusing gamma system, the differences between the calculated and measured absorbed doses were below 1.86%. The ROFs calculated by the TPS were independently confirmed within 2% using EBT3 films and a PTW60016 detector. The point dose differences were below 2.57% and gamma passing rates were above 95.3% using the 2%/1 mm criterion for the E2E tests. The coincidences between the imaging isocenter and the linac/gamma mechanical isocenter were within 0.5 mm. The image quality parameters fully complied with the manufacturer's specifications regarding the CNR, spatial resolution, and uniformity. The multi-modality radiotherapy platform complies with the CAT and AAPM commissioning criteria. The commissioning results demonstrate that this platform performs well in mechanical and dosimetry accuracy.

Automated diagnosis and management of follicular thyroid nodules based on the devised small-dataset interpretable foreground optimization network deep learning: a multicenter diagnostic study.

BACKGROUND: Currently, follicular thyroid carcinoma (FTC) has a relatively low incidence with a lack of effective preoperative diagnostic means. To reduce the need for invasive diagnostic procedures and to address information deficiencies inherent in a small dataset, we utilized interpretable foreground optimization network deep learning to develop a reliable preoperative FTC detection system. METHODS: In this study, a deep learning model (FThyNet) was established using preoperative ultrasound images. Data on patients in the training and internal validation cohort ( n =432) were obtained from Ruijin Hospital, China. Data on patients in the external validation cohort ( n =71) were obtained from four other clinical centers. We evaluated the predictive performance of FThyNet and its ability to generalize across multiple external centers and compared the results yielded with assessments from physicians directly predicting FTC outcomes. In addition, the influence of texture information around the nodule edge on the prediction results was evaluated. RESULTS: FThyNet had a consistently high accuracy in predicting FTC with an area under the receiver operating characteristic curve (AUC) of 89.0% [95% CI 87.0-90.9]. Particularly, the AUC for grossly invasive FTC reached 90.3%, which was significantly higher than that of the radiologists (56.1% [95% CI 51.8-60.3]). The parametric visualization study found that those nodules with blurred edges and relatively distorted surrounding textures were more likely to have FTC. Furthermore, edge texture information played an important role in FTC prediction with an AUC of 68.3% [95% CI 61.5-75.5], and highly invasive malignancies had the highest texture complexity. CONCLUSION: FThyNet could effectively predict FTC, provide explanations consistent with pathological knowledge, and improve clinical understanding of the disease.

A novel X-Ray and γ-Ray combination strategy for potential dose escalation in patients with locally advanced pancreatic cancer.

BACKGROUND: Treatment of locally advanced pancreatic cancer (LAPC) has long been calling for advances in technology of radiotherapy. Patients who received radiotherapy still had high risks of local recurrence, while suffering from gastrointestinal side effects. Based on the inherent characteristics of the x-ray and γ-Ray radiation techniques, here we proposed and investigated an unexplored radiation therapy. PURPOSE: To investigate the potential clinical benefit of a novel x-ray and γ-Ray combination radiation technique in patients with LAPC. METHODS: Retrospective intensity-modulated radiotherapy (IMRT) treatment plans of 10 LAPC patients were randomly selected to compare with dual-modality plans. The prescribed dose to PGTV was 60.2 Gy. The PGTV dose was further escalated in dual-modality plan while maintaining clinically tolerable dose to organs at risk (OARs). Dosimetric comparisons were made and analyzed for three treatment plans (tomotherapy, standard dual-modality plan, escalated dual-modality plan) to assess the ability to increase dose to target volume while minimizing dose in adjacent OARs. Finally, radiobiological models were utilized for comparison. RESULTS: All strategies resulted in dosimetrically acceptable plans. Dual-modality plans were present with similar conformity index (CI) and significantly lower gradient index (GI) compared with tomotherapy (3.64 ± 0.37 vs. 4.14 ± 0.61, p = 0.002; 3.64 ± 0.42 vs. 4.14 ± 0.61, p = 0.003). Dmean of PGTV (65.46 ± 3.13 vs. 61.56 ± 1.00, p = 0.009; 77.98 ± 5.86 vs. 61.56 ± 1.00, p < 0.001) and PCTV (55.04 ± 2.14 vs. 53.93 ± 1.67, p = 0.016; 58.24 ± 3.24 vs. 53.93 ± 1.67, p = 0.001) were significantly higher, while Dmean of the stomach was reduced in both dual-modality plans (17.98 ± 10.23 vs. 19.34 ± 9.75, p = 0.024; 17.62 ± 9.92 vs. 19.34 ± 9.75, p = 0.040). The lower V30Gy in the liver (4.83 ± 5.87 vs. 6.23 ± 6.68, p = 0.015; 4.90 ± 5.93 vs. 6.23 ± 6.68, p = 0.016) and lower V45Gy of the small intestine (3.35 ± 3.30 vs. 4.06 ± 3.87, p = 0.052) were found in dual-modality plans. Meanwhile, radiobiological models demonstrated higher probability of tumor control (29.27% ± 9.61% vs. 18.34% ± 4.70%, p < 0.001; 44.67% ± 18.16% vs. 18.34% ± 4.70%, p = 0.001) and lower probability of small intestine complication (2.16% ± 2.30% vs. 1.25% ± 2.72%, p = 0.048) in favor of dual-modality strategy. CONCLUSIONS: A novel dual-modality strategy of x-ray and γ-Ray combination radiation appears reliable for target dose escalation and normal tissue dose reduction. This strategy might be beneficial for local tumor control and the protection of normal organs in patients with LAPC.

Genome-Wide Analysis of Soybean Lateral Organ Boundaries Domain Gene Family Reveals the Role in Phytophthora Root and Stem Rot.

The plant-specific lateral organ boundaries (LOB) domain (LBD) proteins, a family of transcription factors, play important roles in plant growth and development, as well as in responses to various stresses. However, little is known about the functions of LBD genes in soybean (Glycine max). In this study, we investigated the evolution and classification of the LBD family in soybean by a phylogenetic tree of the LBD gene family from 16 species. Phylogenetic analysis categorized these proteins into two classes (Class I and Class II) with seven subgroups. Moreover, we found that all the 18 LBD ancestors in angiosperm were kept in soybean, common bean genomes, and genome-wide duplication, suggesting the main force for the expansion of LBD from common bean to soybean. Analysis of gene expression profiling data indicated that 16 GmLBD genes were significantly induced at different time points after inoculation of soybean plants (cv. Huachun 6) with Phytophthora sojae (P. sojae). We further assessed the role of four highly upregulated genes, GmLBD9, GmLBD16, GmLBD23, and GmLBD88, in plant defense in soybean hairy roots using the transient overexpression and knockdown assays. The results showed that GmLBD9 and GmLBD23 negatively regulate plant immunity against P. sojae, whereas GmLBD16 and GmLBD88 positively manipulate plant immunity against P. sojae. Collectively, our findings expand our knowledge of the origin and evolution of the GmLBD gene family in soybean and promote the potential application of these genes in soybean genetic improvement.

Unveiling significance of Ca2+ ion for start-up of aerobic granular sludge reactor by distinguishing its effects on physicochemical property and bioactivity of sludge.

Almost all of the aerobic granular sludge (AGS) reactors were fed on certain amounts of Ca2+ ion, but whether and why it was necessary for reactor start-up remain unknown. Herein, this study conducted a set of comparative experiments in three AGS reactors, which were operated in parallel with Ca2+ addition in R3, hydroxyapatite (HAP) addition in R1, and without any forms of Ca addition in R2. Results showed that R3 not only achieved the complete granulation of sludge, but exhibited superior performance of COD and nutrient removal. In contrast, R1 had a slightly quicker granulation rate than R3 (R1: 0.07 day-1; R3: 0.06 day-1), but the formed granules could not efficiently degrade pollutants. In R2, both sludge granulation and pollutants removal did not proceed normally. Further investigations found that the Ca2+ ion acted in three ways: (1) it increased inorganic composition of sludge to promote granulation; (2) the transformed HAP strengthened stability of granular structure; (3) it ensured bioactivity of granules by driving enrichment of functional microbes and synthesis of metabolism enzymes. Overall, this study systemically proved significance of Ca2+ ion for the start-up of AGS reactors and its influencing mechanisms on different properties of granules.

Associations Among Workplace Bullying, Resilience, Insomnia Severity, and Subjective Wellbeing in Chinese Resident Doctors.

BACKGROUND: Although workplace bullying is common among medical workers, its associations with insomnia severity and subjective wellbeing are still unclear. Our study aimed to investigate these associations among resident doctors who are more vulnerable to both workplace bullying and insomnia. METHODS: We conducted a cross-sectional survey of 1,877 resident doctors from 12 hospitals across 7 administrative regions in China. Workplace bullying, resilience, insomnia severity, and subjective wellbeing were evaluated by the Negative Acts Questionnaire-Revised (NAQ-R), the Chinese version of the Connor-Davidson Resilience Scale-10-item (CD-RISC-10), the Insomnia Severity Index, and the Index of Wellbeing, respectively. Further, a logistic regression analysis was used to analyze factors associated with insomnia. In addition, structural equation modeling (SEM) was applied to examine the associations among workplace bullying, resilience, insomnia severity, and subjective wellbeing. RESULTS: In the present study, the rates of workplace bullying and insomnia were 51.4 and 33.2%, respectively. Workplace bullying (OR = 1.056, p < 0.001) and poor resilience (OR = 0.957, p < 0.001) were the factors associated with insomnia after controlling the confounding variables. Further, SEM of the present study revealed a direct relationship between workplace bullying and subjective wellbeing (std-ß = -0.223, p < 0.001). In addition, insomnia severity (std-ß = -0.071, p < 0.001) and resilience (std-ß = -0.092, p < 0.001) can individually or collectively (std-ß = -0.008, p < 0.001) mediate the indirect associations between workplace bullying and subjective wellbeing. However, resilience was found to act as a moderator only in the direct association between workplace bullying and subjective wellbeing. CONCLUSIONS: Workplace bullying and poor resilience were the factors associated with insomnia. Further, greater resilience acted as a buffer in the direct association between workplace bullying and subjective wellbeing, whereas both insomnia severity and resilience were critical mediators in the indirect associations between them.

KDM1A/LSD1 as a promising target in various diseases treatment by regulating autophagy network.

Epigenetics refers to alterations in gene expressions that are reversible and stable, but do not involve changes in DNA sequences. In recent years, an increasing number of studies have shown that epigenetics plays a critical role in autophagy, which can be schematized as a biological process comprising of the following steps: autophagy signal activation, autophagic vesicle elongation, autophagosome maturation and autophagosome-lysosome fusion. As previously reported, autophagy can maintain intracellular homeostasis and autophagy dysfunction will lead to various diseases. For instance, the abnormal expression of genes involved in autophagy can result in the occurrence of many cancers and atherosclerosis. It is also well known that epigenetic modifications can affect autophagy related genes expressions and modulate other signaling molecular involved in autophagy. As an important epigenetic enzyme, LSD1 (lysine specific demethylase 1) plays an essential role in modulating autophagy. On one hand, LSD1 directly regulates autophagy-related genes expressions, including ATGs, Beclin-1, LC3 and SQSTM1/p62. On the other hand, inhibition of LSD1 can activate autophagy through regulating the activities of some other proteins such as p53, SESN2, mTORC1 and PTEN. Since autophagy activation is tightly related to the occurrence of various diseases and can be induced by LSD1 inhibition, development of LSD1 inhibitors will provide a new direction to treat such diseases. In this review, we described the mechanisms by which LSD1 regulates autophagy in different manners and how autophagic dysfunction leads to diseases occurrence. In addition, some LSD1 inhibitors used to treat diseases through modulating autophagy are also summarized in our review.

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

Tissue-based metabolomics reveals metabolic signatures and major metabolic pathways of gastric cancer with help of transcriptomic data from TCGA.

PURPOSE: The aim of the present study was to screen differential metabolites of gastric cancer (GC) and identify the key metabolic pathways of GC. METHODS: GC (n=28) and matched paracancerous (PC) tissues were collected, and LC-MS/MS analysis were performed to detect metabolites of GC and PC tissues. Metabolite pathways based on differential metabolites were enriched by MetaboAnalyst, and genes related to metabolite pathways were identified using the KEGGREST function of the R software package. Transcriptomics data from The Cancer Genome Atlas (TCGA) was analyzed to obtain differentially expressed genes (DEGs) of GC. Overlapping genes were acquired from metabonimics and transcriptomics data. Pathway enrichment analysis was performed using String. The protein expression of genes was validated by the Human Protein Atlas (HPA) database. RESULTS: A total of 325 key metabolites were identified, 111 of which were differentially expressed between the GC and PC groups. Seven metabolite pathways enriched by MetaboAnalyst were chosen, and 361 genes were identified by KEGGREST. A total of 2831 DEGs were identified from the TCGA cohort. Of these, 1317 were down-regulated, and 1636 were up-regulated. Twenty-two overlapping genes were identified between genes related to metabolism and DEGs. Glycerophospholipid (GPL) metabolism is likely associated with GC, of which AGPAT9 and ETNPPL showed lower expressed in GC tissues. CONCLUSIONS: We investigated the tissue-based metabolomics profile of GC, and several differential metabolites were identified. GPL metabolism may affect on progression of GC.

Design and synthesis of new indole containing biaryl derivatives as potent antiproliferative agents.

A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 µM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.

Cullin-RING Ligases as Promising Targets for Gastric Carcinoma Treatment.

Gastric carcinoma has serious morbidity and mortality, which seriously threats human health. The studies on gastrointestinal cell biology have shown that the ubiquitination modification that occurs after protein translation plays an essential role in the pathogenesis of gastric carcinoma. Protein ubiquitination is catalyzed by E3 ubiquitin ligase and can regulate various substrate proteins in different cellular pathways. Cullin-RING E3 ligase (CRLs) is a representative of the E3 ubiquitin ligase family, which requires cullin (CUL) neddylation modification for activation to regulate homeostasis of ~20% of cellular proteins. The substrate molecules regulated by CRLs are often involved in many cell progressions such as cell cycle progression, cell apoptosis, DNA damage and repair. Given that CRLs play an important role in modulation of biological activities, so targeting a certain CULs member neddylation may be an attractive strategy for selectively controlling the cellular proteins levels to achieve the goal of cancer treatment. In this review, we will discuss the roles of CULs and Ring protein in gastric carcinoma and summarize the current neddylation modulators for gastric carcinoma treatment.

Features of Lymph Node Metastasis and Structural Recurrence in Papillary Thyroid Carcinoma Located in the Upper Portion of the Thyroid: A Retrospective Cohort Study.

Background: This study aims to reveal the features of lymph node metastasis (LNM) and recurrence in papillary thyroid carcinoma (PTC) tumors located in the upper portion of the thyroid. Methods: A total of 1075 PTC patients were retrospectively reviewed, including 314 patients with a tumor in the upper portion of the thyroid. Another 103 PTC patients with upper portion diagonsis from three clinical centers were included for external validation. Results: The results showed no difference between the patients with a tumor in the upper portion of the thyroid and those with a tumor in the non-upper portion in terms of overall LNM rates. However, patients with a tumor in the upper portion were significantly more prone to LLNM and exhibited a significantly worse recurrence outcome than those with a tumor in other subregions. Multivariate analysis showed that four factors-age no more than 40, maximum tumor diameter no less than1.0 cm, the presence of thyroid capsular invasion, and tumor with ipsilateral nodular goiter-were independent risk factors for LLNM of the tumor in the upper thyroid. A predictive risk-scoring model was established based on these factors. Conclusions: Patients with PTC located in the upper portion may have an exclusive lymphatic drainage pathway to the lateral neck region and are more prone to suffer from LLNM and tumor recurrence than those with a tumor located in other subregions. A new postoperative strategy selection flow chart was established based on our newly created risk-scoring model that can effectively predict the individualized possibility of LLNM for PTC patients with a tumor in the upper portion.

Fabrication of TiO2/Fe2O3/CdS systems: effects of Fe2O3 and CdS content on superior photocatalytic activity.

A heterostructured material of CdS and Fe2O3 nanoparticle-modified TiO2 nanotube array (NTA) photoelectrode (TiO2/Fe2O3/CdS) is reported in this work. TiO2/Fe2O3 was prepared by annealing TiO2 NTAs pre-loaded with Fe(OH)3, which was uniformly clung to TiO2 NTAs using sequential chemical bath deposition (S-CBD). Subsequently, CdS nanoparticles were deposited on TiO2/Fe2O3 using the successive ion layer adsorption and reaction (SILAR) technique. Three-dimensional (3D) TiO2/Fe2O3/CdS samples generated a photocurrent of approximately 4.92 mA cm-2, with a photoconversion efficiency of 4.36%, which is more than 20 times higher than that of bare TiO2 NTAs (0.22%) and 6 times that of TiO2/Fe2O3 (0.71%). The photocatalytic activity was evaluated by the degradation of p-nitrophenol (PNP) under visible light (λ > 420 nm). The TiO2/Fe2O3/CdS exhibited the best photocatalytic activity among all samples. Almost all PNP was degraded by TiO2/Fe2O3/CdS within 120 min. The enhancement of photocatalytic activity could be attributed to the promoted photo-induced electron and hole separation and migration on the basis of photoluminescence spectra, photocurrent measurements, and open-circuit photovoltage responses. In addition, the newly synthesized TiO2/Fe2O3/CdS can maintain high photocatalytic efficiency for five reuse cycles. Our findings provide a new idea for the low cost synthesis of high performance photocatalysts for the photodegradation of organic pollutants in aqueous solution.

The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal Farnesoid X Receptor Signaling Pathway and Inhibition of Hepatic Gluconeogenesis.

Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.