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Background: Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second- highest cause of cancer death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. Methods: Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). Results: AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. Conclusion: AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.

Five new triterpenoids named as euphatexols C - G (1-5) were isolated from the latex of Euphorbia resinifera. Their chemical structures were determined by extensive spectroscopic analysis, including IR, HRMS, 1 D and 2 D NMR data. Compounds 1-5 showed moderate anti-inflammatory activity with IC50 values of 22.30, 48.04, 21.89, 38.15 and 41.15 μM, respectively.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients., Graphical abstract JOSD2, a deubiquitinating enzyme, increases YAP/TAZ abundance and reinforces their signaling through the cleavage of polyubiquitin chains, observably contributing to cholangiocarcinoma progression.Image 1

Immunotherapy is regarded as a potential strategy to combat cancer, especially when immunotherapy is combined with appropriate chemotherapy. However, the immunosuppressive tumor microenvironment (TME) and serious side effects extremely limit the application of immunotherapy. Herein, a self-stabilized hyaluronic acid nanoparticle is synthesized for tumor-targeted delivery of doxorubicin (DOX), cisplatin (CDDP), and resiquimod (R848) in osteosarcoma immunochemotherapy, which is referred to as CDDPNPDOX&R848. CDDPNPDOX&R848 exhibits sufficient stability, great pH responsibility, and brilliant tumor-targeting accumulation in vivo, which make it suitable for further in vivo applications. After intravenous injection, CDDPNPDOX&R848 can release the loaded cargoes under the acidic TME continuously. DOX can induce tumor cell apoptosis in combination with CDDP and trigger immunogenic cell death. More importantly, the immune-activated TME created by R848 can facilitate tumor-associated antigen presentation and antitumor immunity elicitation. Benefiting from the synergistic effect of chemotherapy and immunotherapy, the growth of tumors and lung metastasis was greatly inhibited by CDDPNPDOX&R848 in the K7M2 orthotopic osteosarcoma mouse model. Thus, this intelligent codelivery platform might be a competitive candidate for osteosarcoma immunochemotherapy.

OBJECTIVES The aims of this study were to analyze the continuous glucose monitoring (CGM) profiles of patients with insulinoma before and after treatment with endoscopic ultrasound-guided ethanol injection and assess the value of CGM in curative effect evaluating. METHODS We included 8 patients, and CGM was performed for 3 to 5 days before and after treatment. RESULTS The proportion of monitoring points at which the glucose level was lower than 3.9 mmol/L after treatment decreased in patient 5 (from 4% to 3%) and patient 8 (from 30% to 12%), whereas the proportion increased in patient 1 (from 1% to 16%), patient 3 (from 5% to 23%), and patient 7 (from 7% to 63%). There was no mean significant difference between CGM values (5.75 [standard deviation, 2.49] mmol/L) and self-monitoring of blood glucose values (5.76 [standard deviation, 2.32] mmol/L) (P > 0.05). Pearson correlation analysis showed positive correlation between CGM values and self-monitoring of blood glucose values (r = 0.88, P < 0.05). Clarke Error Grid Analysis showed that 91.5% of pairs were located in areas A and B. CONCLUSIONS Continuous glucose monitoring is useful for detecting hypoglycemia and evaluating curative effect, but the correction of fingertip blood glucose is necessary when the blood glucose is relatively low.

The production and emission of short-chain perfluoroalkyl acids (PFAAs) has increased over the years to replace long-chain PFAAs, leading to frequent detection in the environment and raising global concerns about the potential impacts on human health. In this study, the specific urine levels of 10 PFAAs were obtained from 189 children (age 8-12 years) from two primary schools located in urban and suburban areas of Shanghai in 2019, and the contributions of dietary factors were investigated. Perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), and perfluorobutane sulfonate (PFBS) were detected in 100%, 99.5%, and 87.3% of the samples, with median concentrations of 20.20 ng/L, 46.50 ng/L, and 20.95 ng/L, respectively. The most abundant PFAA was perfluorooctanoic acid (PFOA), with a median concentration of 78.90 ng/L. The concentration of ∑PFAAs ranged from 61.10 to 4108.93 ng/L, with a median concentration of 253.12 ng/L. Children aged 8-9 years had higher median levels of PFBS, perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) than children aged 10-12 years. Obese/overweight children had lower levels of PFHpA, PFBS, and PFOS. The intake of red meats, tubers, sugared beverages, fish and seafood, and eggs contributed to higher concentrations of PFAAs, while frequent intake of poultry and soy milk was associated with lower PFAA concentrations.

Age-related macular degeneration (AMD) is one of the major causes of blindness, and the incidence of this disease has been increasing in recent years. To investigate the association between the single nucleotide polymorphisms (SNPs) of the high temperature requirement factor A-1 (HTRA1) and complement factor H (CFH) genes and susceptibility to AMD in Ningbo, China. Ninety-eight patients with AMD and seventy-three controls were recruited at the Sixth Hospital of Ningbo from August 2017 to April 2019 in China. Genomic DNA was extracted from the venous blood provided by the hospital, and the genotypes of the AMD susceptibility genes CFH and HTAR1 were detected by polymerase chain reaction and sequenced directly. The SNPs rs11200638 on the HTRA1 gene and rs3753394 on the CFH gene were selected for genotype and association analysis. The correlations between the different genotypes of HTRA1 and CFH and AMD were analysed by the Chi-squared test. All the genotypes adhered to the Hardy–Weinberg equilibrium. There were three genotypes (AA, AG and GG) in HTRA1 (rs11200638). The differences in genotypes and allele frequency between the AMD group and the control group were statistically significant (P 0.05). The rs11200638 SNP of the HTRA1 gene is associated with AMD, and the AA genotype is a risk factor for AMD in the Ningbo population. There is no significant correlation between the rs3753394 SNP of the CFH gene and AMD.

Context Extreme insulin resistance is caused by genetic defects intersecting with the insulin action pathway or by the insulin receptor antibodies. Insulin autoimmune syndrome (IAS) is not considered one of the causes of extreme insulin resistance. Objective This work aimed to expand the current knowledge of extreme insulin resistance and to propose the diagnostic criteria and management strategy of a novel type of extreme insulin resistance. Methods A patient with IAS never experienced hypoglycemia but had persistent hyperglycemia and extreme insulin resistance with treatment with 200 U of intravenous insulin per day. Immunoreactive insulin (IRI), free insulin, and total insulin were measured. The ratio of free insulin to total insulin (insulin-free ratio, IFR) was calculated. Results Extreme insulin resistance has not been reported to be caused by IAS. At admission, IRI and free insulin were undetectable in our patient; total insulin was more than 20 160 pmol/L; and the IFR was lower than 0.03% (control, 90.9%). After adding 500 U porcine insulin to the precipitate containing insulin antibodies, the IRI was still undetectable. Since the patient started glucocorticoid therapy, the free insulin has gradually increased to 11.16 pmol/L, his total insulin has decreased to 5040 pmol/L, and the IFR has increased to 18.26%. Intravenous insulin was stopped, with good glycemic control. Conclusion High-affinity insulin autoantibodies with a large capacity can induce a novel type of extreme insulin resistance characterized by extremely high total insulin and very low free insulin levels. The IFR can be used to evaluate therapeutic effects.

Steady State Motion Visual Evoked Potential (SSMVEP)-based Brain Computer Interface (BCI) is widely studied and has been used to varies of occasions on account of its good performance, mild stimulation, and free of additional training. We design a trolley control system based on SSMVEP signals and observe a phenomenon named “BCI Illiterate,” in which case some subjects present unsatisfactory performance with low classification accuracies. In order to cope with this challenging problem in real-world contexts, we introduce a deep learning (DL) method. The method allows improving the accuracies for both EEG literate and EEG illiterate. In particular, we firstly conduct SSMVEP experiments to obtain EEG signals from 10 subjects, including 5 EEG literates and 5 EEG illiterates. Then we construct a convolutional neural network with long short-term memory (CNN-LSTM) framework, which allows extracting the spectral, spatial, and temporal features of EEG signals, to realize the high classification accuracies of SSMVEP signals. The results show that DL method can reach 96.83% and 91.86% for EEG literate and EEG illiterate respectively, which are 12.68% and 31.08% higher than the results of traditional methods. These results indicate that DL method is not only suitable for EEG literate, but more importantly, can greatly improve the performance for EEG illiterate, which finally can enhance the robustness and universality of the SSMVEP-based BCI.

Bach2 is closely associated with systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells and CD4+ T cells of SLE patients exhibit a decrease of Bach2 expression and an increase in the proportions of Th9 cells. Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in SLE., Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal activation of T cells and caused by an imbalance in the production and clearance of apoptotic cells. We previously showed that the transcription regulator Bach2 regulated abnormal B‐cell activation in SLE. Here, we investigated whether Bach2 was also involved in Th9 cell differentiation in SLE. We found that the proportion of Th9 cells was enhanced in the peripheral blood mononuclear cells (PBMC) of SLE patients. The PBMC and CD4+ T cells of SLE patients exhibited a decrease of Bach2 expression and an increase of IL‐9 expression. Furthermore, Bach2 overexpression significantly repressed the levels of PU.1, IRF4, IL‐9, and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. In addition, Bach2 overexpression inhibited the levels of IL‐9 and Th9 cells, whereas IRF4 upregulation enhanced the levels of IRF4 and IL‐9 and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. The effect of IRF4 up‐regulation was abolished by Bach2 overexpression. In summary, our work suggests that Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in SLE, and thus, Bach2 may be a novel potential target for SLE treatment.

Highlights • Prone position ventilation therapy should be considered when P/F ratio was still below 150mmHg after intubation in patients of COVID-19. • Acute cor pulmonale(ACP) was often complicated with ARDS caused by COVID-19, dobutamine and the prone position ventilation therapy would be effective. • High-Flow nasal cannula(HFNC) oxygen therapy could be as sequential strategy to reduce the risk of reintubation and postextubation respiratory failure, and was safe enough during the current COVID-19 outbreak. • Cardiorespiratory function support therapy was the core of surviving COVID-19, and it was better to start early to achieve good prognosis., Background : An outbreak of acute respiratory illness was proved to be infected by a novel coronavirus, officially named Coronavirus Disease 2019 (COVID-19) from World Health Organization (WHO), was confirmed first in Wuhan, China, and has become endemic worldwide, which was a serious threaten to public health all over the world. Herein, we reported a successful critical case of COVID-19 and shared our experience of treatment, which would do a favor for other COVID-19 patients. Case Summary : A 65-year-old man, Wuhan citizen, was infected by COVID-19, and his pulmonary lesions progressed quickly in five days. On admission to Tongji Hospital, Wuhan, China, the immediate arterial blood gas(ABG) analysis showed the PaO2/FiO2(P/F) ratio was 134.4mmHg, moderate acute respiratory distress syndrome(ARDS) was diagnosed. Emergency tracheal intubation was performed, and the initial ventilator mode and parameters were set up based on the lung-protective ventilation strategy, but the P/F ratio could not be improved, and then the prone position ventilation was carried out for four consecutive days, as long as 16 hours every day, the P/F ratio rose to 180mmHg approximately, which still did not reach to the standard of extubation. And then we found that it was complicated with acute cor pulmonale(ACP) by ultrasound examination, dobutamine and diuretic were used for the treatment of ACP caused by ARDS successfully, and the P/F ratio went up to about 250mmHg. Seven days later after admission, the endotracheal intubation was successfully removed, after extubation, High-Flow nasal cannula(HFNC) oxygen therapy was used as a sequential strategy to prevent reintubation. Ultimately, he was discharged on day 34 after admission. Conclusion : Our case presented the treatment process of a critical COVID-19. Effective therapy was crucial to heal COVID-19, and organ function support therapy, especially the cardiorespiratory function support therapy, was the core of treatment.

Antibiotic resistance is a great concern, which leads to global public health risks and ecological and environmental risks. The presence of antibiotic-resistant genes and antibiotic-resistant bacteria in the environment exacerbates the risk of spreading antibiotic resistance. Among them, horizontal gene transfer is an important mode in the spread of antibiotic resistance genes, and it is one of the reasons that the antibiotic resistance pollution has become increasingly serious. At the same time, free antibiotic resistance genes and resistance gene host bacterial also exist in the natural environment. They can not only affect horizontal gene transfer, but can also migrate and aggregate among environmental media in many ways and then continue to affect the proliferate and transfer of antibiotic resistance genes. All this shows the seriousness of antibiotic resistance pollution. Therefore, in this review, we reveal the sensitive factors affecting the distribution and spread of antibiotic resistance through three aspects: the influencing factors of horizontal gene transfer, the host bacteria of resistance genes and the migration of antibiotic resistance between environmental media. This review reveals the huge role of environmental migration in the spread of antibiotic resistance, and the environmental behavior of antibiotic resistance deserves wider attention. Meanwhile, extracellular antibiotic resistance genes and intracellular antibiotic resistance genes play different roles, so they should be studied separately.

Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.

Filamentous fungi are known as producers of a large array of diverse secondary metabolites (SMs) that aid in securing their environmental niche. Here, we demonstrated that the SMs have an additional role in fungal defence against other fungi: Trichoderma guizhouense, a mycoparasite, is able to antagonize Fusarium oxysporum f. sp. cubense race 4 (Foc4) by forming aerial hyphae that kill the host with hydrogen peroxide. At the same time, a gene cluster comprising two polyketide synthases is strongly expressed. Using functional genetics, we characterized this cluster and identified its products as azaphilones (termed as trigazaphilones). The trigazaphilones were found lacking of antifungal toxicity but exhibited high radical scavenging activities. The antioxidant property of trigazaphilones was in vivo functional under various tested conditions of oxidative stress. Thus, we conclude that the biosynthesis of trigazaphilones serves as a complementary antioxidant mechanism and defends T. guizhouense against the hydrogen peroxide that it produces to combat other fungi like Foc4.

Objective. To explore the relationship between the HER2 gene and PD-1/PD-L1 in gastric cancer and its significance. Methods. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect HER2 protein expression, HER2 gene amplification, and PD-1/PD-L1 expression in 78 cases of gastric cancer. Results. The expression rate of HER2 protein was 43.6% (34/78), of which 19.4% (14/78) were HER2 3+, 14.1% (11/78) were HER2 2+, and 11.5% (9/78) were HER2 1+. The results showed that 19.2% (15/78) of samples had HER2 gene amplification, 3.8% (3/78) of samples had a HER2/CEP17 ratio P < 0.05 ). Conclusions. The combined detection of the HER2 gene and PD-1/PD-L1 in gastric cancer provides an important reference index for the prognosis of gastric cancer and the benefit of targeted antitumor drugs.

The efficacy and safety of secukinumab, an interleukin-17 inhibitor, as systemic treatment for patients with moderate-to-severe psoriasis have been demonstrated, but real-world data pertaining to this is limited in China. To evaluate the efficacy and safety of secukinumab in clinical practice in Chinese psoriasis patients with or without psoriatic arthritis (PsA) and identify potential baseline factors that affect the response of patients to secukinumab treatment. Data from 81 patients treated with secukinumab for at least 16 weeks were analysed in a retrospective observational study. After 16 weeks of treatment with secukinumab, 91.1%, 73%, and 38.3% of patients achieved a PASI 75 (75% improvement based on the Psoriasis Area and Severity Index), PASI 90, and PASI 100, respectively. A significant improvement in the quality of life of patients was also observed. Notably, baseline factors, such as young age, lower BMI, no scalp involvement and absence of concomitant PsA, were associated with better clinical response to secukinumab. Approximately 42% of patients (34/81) experienced adverse events, of which the most common was pruritus. The results demonstrated that secukinumab appears to be an effective treatment alternative for the majority of Chinese plaque psoriasis patients. Baseline factors, including age, BMI, scalp involvement and concomitant presence of PsA, were associated with response to secukinumab.

Background Atherosclerosis can lead to multiple cardiovascular diseases, especially myocardial infarction. Long noncoding RNAs (lncRNAs) are involved in multiple diseases, including atherosclerosis. LncRNA HOXA-AS3 was found to be notably upregulated in atherosclerosis. However, the biological function of HOXA-AS3 during the occurrence and development of atherosclerosis remains unclear. Materials and methods Human vascular endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (oxLDL) to mimic atherosclerosis in vitro. Gene and protein expressions in HUVECs were detected by RT-qPCR and Western blot, respectively. Cell proliferation was tested by CCK-8 and Ki67 staining. Cell apoptosis and cycle were measured by flow cytometry. Additionally, the correlation between HOXA-AS3 and miR-455-5p was confirmed by dual luciferase report assay and RNA pull-down. Finally, in vivo model of atherosclerosis was established to confirm the function of HOXA-AS3 during the development of atherosclerosis in vivo. Results LncRNA HOXA-AS3 was upregulated in oxLDL-treated HUVECs. In addition, oxLDL-induced growth inhibition of HUVECs was significantly reversed by knockdown of HOXA-AS3. Consistently, oxLDL notably induced G1 arrest in HUVECs, while this phenomenon was greatly reversed by HOXA-AS3 siRNA. Furthermore, downregulation of HOXA-AS3 notably inhibited the progression of atherosclerosis through mediation of miR-455-5p/p27 Kip1 axis. Besides, silencing of HOXA-AS3 notably relieved the symptom of atherosclerosis in vivo. Conclusion Downregulation of HOXA-AS3 significantly suppressed the progression of atherosclerosis via regulating miR-455-5p/p27 Kip1 axis. Thus, HOXA-AS3 might serve as a potential target for the treatment of atherosclerosis.

An environmentally friendly method for the determination of testosterone and methyltestosterone by acid–base-induced deep eutectic solvents liquid–liquid microextraction (DES-ABLLME) combining with high-performance liquid chromatography was established. The deep eutectic solvent (DES) consisting of menthol:lauric acid:decanoic acid (3:1:1) can act as both hydrogen bond donor and hydrogen bond acceptor. In this approach, ammonia solution (NH3•H2O) is used as an emulsifier to react with DESs in the extraction process to generate salt and form milky white solution, achieving high extraction efficiency. Hydrochloric acid was used as a phase separator to change the emulsification state and promote the separation of extraction agent from water phase. A series of parameters were optimized including the volume of DES and the emulsifying agent, glucose concentration as well as hydrochloric acid volume. The method was linear in the range 0.5–100 μg mL−1 with a correlation coefficient (R) of 0.9999, and the limits of detection were 0.067 and 0.2 μg mL−1 for testosterone and methyltestosterone, respectively. This method was applied to analyze testosterone and methyltestosterone in milk samples, and the recoveries were between 89.2 and 108.2%.

Dysregulated transcription factors (TFs) fuel aberrant gene expression networks, resulting in cell overproliferation, migration, and immunosuppression. Given that TFs are regarded to have vital roles in tumors, various approaches are exploited to modulate their activities. Nevertheless, except for some ligand-binding nuclear receptors, most TFs are still considered 'undruggable' targets. Responding to extra- or intracellular stimuli, TFs are decorated with an array of post-translational modifications (PTMs) to regulate their subcellular localizations, protein-protein/DNA interactions, and stability. These PTMs orchestrate the multiple functions of TFs, thus offering numerous potential targets. In this review, we systematically review emerging concepts and effective agents in PTMs-associated TF-targeting, which could provide paradigms for cancer treatment.

This study assessed the effects of different electric current densities on the calcification and photosynthetic physiology of a massive, colonial stony coral species. Coral survivorship, calcification rate, and photosynthetic parameters (zooxanthellae density and chlorophyll fluorescence) were measured to determine the physiological and photosynthetic performance of Galaxea fascicularis after exposure to different electric current densities. After 60 days of treatment, survival of G. fascicularis was higher at low electric current density (10 mA m−2) than in the control and at high electric current density (100 mA m−2). Electric current did not alter zooxanthellae densities, but did enhance the photosynthetic processes (e.g. maximum electron transport rates (rETRm), and maximum quantum yield (Fv/Fm)) within 45 days. Coral calcification rate increased in response to low electric current density up to 30 days, but the effects of the electric current were not significant after a longer period of treatment. Overall, our results indicated that mineral accretion technology with appropriate electric current density conditions was somewhat helpful in enhancing coral growth, and thus this technique may be used in the restoration and management of massive stony coral reefs.

The aim of this study was to investigate the correlations between serum calcium and clinical outcomes in patients with coronavirus disease 2019 (COVID-19). In this retrospective study, serum calcium levels, hormone levels and clinical laboratory parameters on admission were recorded. The clinical outcome variables were also recorded. From February 10 to February 28, 2020, 241 patients were enrolled. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, and median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positively correlated with VD levels (P =0.004) but negatively correlated with PTH levels (P =0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidences of organ injury and septic shock, and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P

Two new lathyrane-type diterpenoids, jatropodagins A and B (1 and 2), and five known analogues (3–7), were isolated from the stems of Jatropha podagrica. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all the lathyrane-type diterpenoids (1–7) were evaluated against two human osteosarcoma cell lines (Saos-2 and MG-63). Compound 1 exhibited significant cytotoxic effects against Saos-2 and MG-63 with IC50 values of 8.08 and 14.64 μM, respectively. The IC50 values for the positive control 5-FU against the Saos-2 and MG-63 cell lines were 19.01 and 25.00 μM, respectively. Morphological features of apoptosis activities were evaluated in 1-treated Saos-2 cells and the results confirmed apoptosis in a dose-dependent manner.

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of hepatocellular carcinoma in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in hepatocellular carcinoma patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in hepatocellular carcinoma cells and provides a rationale for potential therapeutic interventions in the treatment of patients with hepatocellular carcinoma harboring a high level of YAP/TAZ. Significance: These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment.

Low-concentration gelatin methacryloyl (GelMA) hydrogels have been found to be promising cell-laden bioinks with excellent cell viability. Herein, we report a strategy that accurately deposits cell-containing bioinks at 5% (w/v) GelMA using extrusion three-dimensional (3D) bioprinting technology by utilizing its photo-crosslinkable and thermosensitive properties without the need for any sacrificial materials. During the 3D printing process, regular, smooth microfibers were formed without any discontinuity of extrusion or clogging, and photo-crosslinking was then used to stabilize the printed GelMA structure. After printing, the scaffolds were cultured in a chondrogenic medium to evaluate their significant roles in directing the behaviors of bone mesenchymal stem cells (BMSCs). Evidence of chondrogenic differentiation was demonstrated by Alcian blue staining and immunofluorescence (Col2a1) as well as the expression of chondrogenic genes. Finally, after platelet-rich plasma treatment, the in vivo effects of the BMSCs on cartilage regeneration on the thigh muscles of female nude mice were measured by using immunohistochemical techniques. The results showed that with this strategy, GelMA bioink displays excellent printability and a high cell survival rate. In vitro and in vivo, the cell-laden scaffold successfully regenerated mature cartilage via a cartilage-specific extracellular matrix, which seems to be suitable for cartilage regeneration and repair.

Purpose Long noncoding RNAs (lncRNAs) in body fluids have been considered as promising novel biomarkers for tumor-related diseases. The present study aimed to investigate the expression level of lncRNA NONHSAT053785 in serum and its correlation with clinical characteristics of hepatocellular carcinoma (HCC) patients. Methods The droplet digital PCR (ddPCR) was used to measure the serum levels of NONHSAT053785 in 112 HCC patients, 96 chronic hepatitis B (CHB) patients, and 99 healthy controls (HC). The correlation between NONHSAT053785 and clinical characteristics was analyzed by chi-square test and Spearman correlation test. The risk factors of intrahepatic metastasis (IM) were detected by univariate and multivariate analyses. Furthermore, the diagnostic value of NONHSAT053785 in HCC and its predictive ability in IM were evaluated by the receiver operating characteristic (ROC) curves. Results The level of NONHSAT053785 was significantly increased in the serum of HCC patients and was higher in HCC patients with IM as compared to those without. Additionally, the expression level of NONHSAT053785 was significantly related to IM, Child-Pugh classification, and peripheral blood indicators such as liver metabolic enzymes and positively correlated to IM, Barcelona Clinic Liver Cancer (BCLC) staging, and some peripheral blood indicators. Furthermore, the serum NONHSAT053785 was indicated as an independent predictor for IM in the elderly, non-smoking, drinking, and tumor size ≥5 cm subjects. The area under the ROC curve (AUC) was 0.801 (P

Annular epidermolytic ichthyosis (AEI) is a rare autosomal dominant ichthyosis that was recently described in 10 separate families in the English literature. There are no reports on the phenotypic heterogeneity of AEI. We investigated, for the first time, a large Chinese AEI pedigree exhibiting interfamilial phenotypic heterogeneity. We collected clinical data and DNA from the members of the family, and skin lesions were obtained from two patients with different phenotypes. Skin imaging examinations were performed. Whole-exome sequencing (WES) and Sanger sequencing were used to detect gene mutations. The characteristic features of granular layer degeneration in the two biopsies were verified via histological methods. The missense mutation c.1436T > Cin KRT1 was detected in all nine patients. This study demonstrates that AEI may present with different clinical phenotypes and that mutation analysis for suspected cases is necessary to obtain a precise diagnosis.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of NOTCH1 are observed in most T-ALL cases, these mutations alone are not sufficient to drive the full development of T-ALL. β-Arrestins (ARRB) are versatile and multifunctional adapter proteins that regulate diverse cellular functions, including promoting the development of cancer. However, the role of ARRBs in T-ALL has largely remained elusive. In this study, we showed that ARRB1 is expressed at low levels in assayed T-ALL clinical samples and cell lines. Exogenous ARRB1 expression inhibited T-ALL proliferation and improved the survival of T-ALL xenograft animals. ARRB1 facilitated NOTCH1 ubiquitination and degradation through interactions with NOTCH1 and DTX1. Mechanistically, the oncogenic miRNA (oncomiR) miR-223 targets the 3′-UTR of ARRB1 (BUTR) and inhibits its expression in T-ALL. Furthermore, overexpression of the ARRB1-derived miR-223 sponge suppressed T-ALL cell proliferation and induced apoptosis. Collectively, these results demonstrate that ARRB1 acts as a tumor suppressor in T-ALL by promoting NOTCH1 degradation, which is inhibited by elevated miR-223, suggesting that ARRB1 may serve as a valid drug target in the development of novel T-ALL therapeutics. Significance: These findings highlight a novel tumor suppressive function of the adaptor protein β-arrestin1 in T-ALL.