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Objective: Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune cells., Design and Methods: Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape., Results: Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples., Conclusions: Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG., Competing Interests: Conflict of interest: the authors have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Due to its lightweight, high strength, good machinability, and low cost, aluminum alloy has been widely used in fields such as aerospace, automotive, electronics, and construction. Traditional manufacturing processes for aluminum alloys often suffer from low material utilization, complex procedures, and long manufacturing cycles. Therefore, more and more scholars are turning their attention to the laser powder bed fusion (LPBF) process for aluminum alloys, which has the advantages of high material utilization, good formability for complex structures, and short manufacturing cycles. However, the widespread promotion and application of LPBF aluminum alloys still face challenges. The excellent printable ability, favorable mechanical performance, and low manufacturing cost are the main factors affecting the applicability of the LPBF process for aluminum alloys. This paper reviews the research status of traditional aluminum alloy processing and LPBF aluminum alloy and makes a comparison from various aspects such as microstructures, mechanical properties, application scenarios, and manufacturing costs. At present, the LPBF manufacturing cost for aluminum alloys is 2-120 times higher than that of traditional manufacturing methods, with the discrepancy depending on the complexity of the part. Therefore, it is necessary to promote the further development and application of aluminum alloy 3D printing technology from three aspects: the development of aluminum matrix composite materials reinforced with nanoceramic particles, the development of micro-alloyed aluminum alloy powders specially designed for LPBF, and the development of new technologies and equipment to reduce the manufacturing cost of LPBF aluminum alloy.

To investigate the regulatory role of the cyp19a1b aromatase gene in the sexual differentiation of largemouth bass (Micropterus salmoides, LMB), we obtained the full-length cDNA sequence of cyp19a1b using rapid amplification of cDNA ends technique. Tissue expression characteristics and feedback with 17-β-estradiol (E 2 ) were determined using quantitative real-time PCR (qRT-PCR), while gonad development was assessed through histological section observations. The cDNA sequence of LMB cyp19a1b was found to be1950 base pairs (bp) in length, including a 5' untranslated region of 145 bp, a 3' untranslated region of 278 bp, and an open reading frame encoding a protein consisting of 1527 bp that encoded 508 amino acids. The qRT-PCR results indicated that cyp19a1b abundantly expressed in the brain, followed by the gonads, and its expression in the ovaries was significantly higher than that observed in the testes (P < 0.05). After feeding fish with E 2 for 30 days, the expression of cyp19a1b in the pseudo-female gonads (XY-F) was significantly higher than that in males (XY-M) (P < 0.05), whereas expression did not differ significantly between XX-F and XY-F fish (P > 0.05). Although the expression of cyp19a1b in XY-F and XX-F fish was not significantly different after 60 days (P>0.05), both exhibited significantly higher levels than that of XY-M fish (P<0.05). Histological sections analysis showed the presence of oogonia in both XY-F and XX-F fish at 30 days, while spermatogonia were observed in XY-M fish. At 60 days, primary oocytes were abundantly observed in both XY-F and XX-F fish, while a few spermatogonia were visible in XY-M fish. At 90 days, the histological sections' results showed that a large number of oocytes were visible in XY-F and XX-F fish. Additionally, the gonads of XY-M fish contained numerous spermatocytes. These results suggest that cyp19a1b plays a pivotal role in the development of ovaries and nervous system development in LMB., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: Neurocytomas (NCs) are rare intracranial tumors that can often be surgically resected. However, disease course is unpredictable in many patients and medical therapies are lacking. We have used whole exome sequencing to explore the molecular etiology for neurocytoma and assist in target identification to develop novel therapeutic interventions., Methods: We used whole exome sequencing (WES) to compare the molecular landscape of 21 primary & recurrent NCs to five normal cerebellar control samples. WES data was analyzed using the Qiagen Clinical Insight program, variants of interest (VOI) were interrogated using ConSurf, ScoreCons, & Ingenuity Pathway Analysis Software to predict their potential functional effects, and Copy number variations (CNVs) in the genes of interest were analyzed by Genewiz (Azenta Life Sciences)., Results: Of 40 VOI involving thirty-six genes, 7 were pathogenic, 17 likely-pathogenic, and 16 of uncertain-significance. Of seven pathogenic NC associated variants, Glucosylceramidase beta 1 [GBA1 c.703T > C (p.S235P)] was mutated in 5/21 (24%), Coagulation factor VIII [F8 c.3637dupA (p.I1213fs*28)] in 4/21 (19%), Phenylalanine hydroxylase [PAH c.975C > A (p.Y325*)] in 3/21 (14%), and Fanconi anemia complementation group C [FANCC c.1162G > T (p.G388*)], Chromodomain helicase DNA binding protein 7 [CHD7 c.2839C > T (p.R947*)], Myosin VIIA [MYO7A c.940G > T (p.E314*)] and Dynein axonemal heavy chain 11 [DNAH11 c.3544C > T (p.R1182*)] in 2/21 (9.5%) NCs respectively. CNVs were noted in 85% of these latter 7 genes. Interestingly, a Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2 [CTDSP2 c.472G > A (p.E158K)] of uncertain significance was also found in > 70% of NC cases., Interpretation: The variants of interest we identified in the NCs regulate a variety of neurological processes including cilia motility, cell metabolism, immune responses, and DNA damage repair and provide novel insights into the molecular pathogenesis of these extremely rare tumors., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Hirschsprung's disease (HD) is a rare congenital digestive tract malformation in children. Roles of long non-coding RNAs (lncRNAs) are highlighted in various human diseases. However, knowledge on lncRNAs in HD is still limited., Methods: The profile of lncRNAs in 8 pairs of normal and stenosed intestinal tissue of HD patients were obtained using microarray analysis. Base on bioinformatics analysis, the level of selected LINC01579-204, NEFL and miR-203a-3p was detected by qRT-PCR in 36 pairs of normal and stenosed intestinal tissue of HD patients. Then the predictive accuracy of LINC01579-204, miR-203a-3p and NEFL level to evaluate the progression of HD patients was analyzed with receiver operating characteristic curve (ROC)., Results: A total of 90 differentially expressed lncRNAs were detected in normal and stenosed intestinal tissue of HD patients (|fold change| ≥ 1.5, p < 0.05). The level of LINC01579-204 and NEFL decreased and miR-203a-3p increased significantly in 36 pairs of stenosed intestinal tissue of HD patients compared to the control. A notable positive correlation was identified between LINC01579-204 and NEFL (r = 0.9681, p < 0.0001). Areas under the ROC curve of the LINC01579-204, miR-203a-3p and NEFL signature were 0.715, 0.777 and 0.829, respectively., Conclusions: LINC01579-204, miR-203a-3p, and NEFL are predicted to play important roles in the progression of HD. LINC01579-204, miR-203a-3p and NEFL had a significant overall predictive ability to identify progression of HD patients. The novel experimental and bioinformatic results achieved in this study may provide new insights into the molecular of HD., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Vagus nerve stimulation (VNS) is a promising neuromodulation technique, which has been demonstrated to promote functional recovery after spinal cord injury (SCI) in our previous study. But the underlying mechanism remains to be explored. Using a compressed SCI model, our present study first demonstrated that activated microglia produce abundant tumor necrosis factor-α (TNF-α) to induce endothelial necroptosis via receptor-interacting protein kinase 1 (RIP1)/RIP3/mixed lineage kinase domain-like protein (MLKL) pathway, thus destroying the blood-spinal cord barrier (BSCB) after SCI. While both TNF-α specifical antibody (infliximab) and necroptosis inhibitor (necrostatin-1) alleviate BSCB disruption. Then our study found that VNS significantly inhibits microglia-derived TNF-α production and reduces expression of p-RIP3 and p-MLKL in endothelial cells. As expected, further results indicated that VNS mitigates the BSCB disruption, thus reducing inflammatory cells infiltration and neural damage. Finally, both electrophysiological evaluation and locomotor test demonstrated that VNS promotes motor function recovery after SCI. In conclusion, our data demonstrated VNS restricts microglia-derived TNF-α to prevent RIP1/RIP3/MLKL mediated endothelial necroptosis, thus alleviating the decisive pathophysiological BSCB disruption to reduce neuroinflammation and neural damage, which ultimately promotes motor function recovery after SCI. Therefore, these results further elaborate that VNS might be a promising therapeutic strategy for SCI. Vagus nerve stimulation prevents microglia-derived TNF-α induced endothelial necroptosis to alleviate blood-spinal cord barrier disruption after spinal cord injury., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Microwave ablation (MWA) is a promising minimally invasive therapy for hepatocellular carcinoma (HCC). However, the efficiency of MWA in treating HCC is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Here we designed an iron-based metal-organic framework nanomedicine (PFP-Apa-MOF) by loading perfluoropentane (PFP) and apatinib (Apa). After being absorbed by HCC, iron could induce ferroptosis. PFP could be activated into bubbles and act as an ultrasound agent for detecting the ablation margin. As an effective antiangiogenic drug, Apa could inhibit tumor residual growth after MWA. The high efficiency of PFP-Apa-MOF was fully demonstrated in vitro and in vivo . The results showed that MWA combined with PFP-Apa-MOF clearly enhanced the ablation efficiency, leading to apparent tumor inhibition, and increased tumor apoptosis and lipid peroxide. PFP-Apa-MOF could play a valuable role in enhancing MWA to achieve better therapeutic efficacy in HCC., Competing Interests: All authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed., (© 2023. The Author(s).)

Background: FK506 binding protein 51 (FKBP5) is a co-chaperone regulator of the glucocorticoid receptor (GR). Recent studies have reported increased FKBP5 mRNA in the circulation from patients with Cushing disease (CD) which returned to comparable levels seen in healthy controls following successful trans -nasal trans -sphenoidal (TNTS) surgical corticotroph tumor removal. However, the expression of circulating FKBP5 mRNA levels in other pituitary tumor subtypes and its specificity to corticotroph tumors is unknown., Methods: Pre-operative blood was collected from consecutive patients undergoing TNTS for pituitary tumors (n = 57) at our center between 2015 and 2019. Total RNA was isolated from whole blood using RiboPure blood RNA isolation kit and real-time qPCR was used to quantitate circulating FKBP5 mRNA expression., Results: Consistent with the prior report, higher circulating FKBP5 mRNA levels were observed in 20 patients with CD prior to surgical tumor removal, compared to 21 healthy controls (p < 0.0005) and compared to 8 patients harboring gonadotroph pituitary tumors (p < 0.05) and 6 patients with silent corticotroph pituitary tumors (p < 0.05). However, circulating FKBP5 mRNA levels were higher in 10 patients with prolactin (PRL)-secreting pituitary tumors compared to healthy controls (p < 0.05), and did not differ between patients with CD and patients with growth hormone secreting tumors (GH-omas)., Conclusions: Although we confirm that circulating FKBP5 mRNA is higher in patients with corticotroph tumors compared to healthy subjects, measurement of circulating FKBP5 does not appear to be helpful to distinguish corticotroph tumors from other pituitary tumor sub-types., (© 2022 Published by Elsevier Ltd.)

Background: Previous studies have failed to investigate the specific effects of advanced age on survival outcomes by considering the Charlson Comorbidity Index (CCI) and age permutation in patients with T1a renal cell carcinoma (T1a RCC) treated by microwave ablation (MWA). Notably, RCC guidelines recommended radiofrequency ablation (RFA) and active surveillance (AS) are both treatment options for elderly T1a RCC, but whether MWA is superior to AS in light of higher heating efficiency and larger ablation zone compared with RFA is not clear. This study aimed to investigate the specific effects of advanced age on survival outcomes of T1a RCC patients stratified by CCI score and indicate better intervention for elderly T1a RCC between MWA and AS., Methods: This was a retrospective study. We retrospectively reviewed 237 patients with T1a RCC who had undergone MWA over the last 16 years. Data were analyzed by Cox regression and Landmark analysis. Interaction tests and propensity score matching were used to account for potential biases. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of patients ≥75 years in our study with corresponding figures from 4251 counterparts undergoing AS in published articles., Results: Using patients ＜75 years with a CCI ≤2 as a reference, the hazard ratio (HR) and 95% confidence interval (CI) of OS for patients＜75 years with a CCI ≥3, patients ≥75 years with a CCI ≤2, and patients ≥75 years with CCI ≥3, were 2.954 (1.139-7.663), 3.48 (1.487-8.146), and 3.357 (1.162-9.698), respectively. The adverse effect of an age ≥75 years on OS was attenuated in patients with a CCI ≥3. The attenuation lasted for 62.5 months of follow-up ( P  = .017). Notably, advanced age exerted a protective effect on progression-free survival (PFS) in patients with a CCI ≥3, increasing the 8-year PFS from 67.8% to 100% ( P  = .049). Relative to 1-, 3-, 5-, and 8-year survival data for patients aged ≥75 undergoing AS, the OS rates for 5-year follow-up were always better in MWA. However, beyond 5 years, the OS rates dropped to levels that were similar to AS., Conclusions: Advanced age exerts adverse effects and significantly protective effects on OS and PFS, respectively, in T1a RCC patients with a CCI ≥ 3. According to our study, elderly patients with T1a RCC underwent radical MWA may yield a better medium-term OS relative to AS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Neurocytomas are rare low-grade brain tumors predominantly affecting young adults, but their cellular origin and molecular pathogenesis is largely unknown. We previously reported a sellar neurocytoma that secreted excess arginine vasopressin causing syndrome of inappropriate anti-diuretic hormone (SIADH). Whole exome sequencing in 21 neurocytoma tumor tissues identified somatic mutations in the plant homeodomain finger protein 14 (PHF14) in 3/21 (14%) tumors. Of these mutations, two were missense mutations and 4 caused splicing site losses, resulting in PHF14 dysfunction. Employing shRNA-mediated knockdown and CRISPR/Cas9-based knockout approaches, we demonstrated that loss of PHF14 increased proliferation and colony formation in five different human, mouse and rat mesenchymal and differentiated cell lines. Additionally, we demonstrated that PHF14 depletion resulted in upregulation of platelet derived growth factor receptor-alpha (PDGFRα) mRNA and protein in neuroblastoma SHSY-5Y cells and led to increased sensitivity to treatment with the PDGFR inhibitor Sunitinib. Furthermore, in a neurocytoma primary culture harboring splicing loss PHF14 mutations, overexpression of wild-type PHF14 and sunitinib treatment inhibited cell proliferation. Nude mice, inoculated with PHF14 knockout SHSY-5Y cells developed earlier and larger tumors than control cell-inoculated mice and Sunitinib administration caused greater tumor suppression in mice harboring PHF-14 knockout than control SHSY-5Y cells. Altogether our studies identified mutations of PHF14 in 14% of neurocytomas, demonstrate it can serve as an alternative pathway for certain cancerous behavior, and suggest a potential role for Sunitinib treatment in some patients with residual/recurrent neurocytoma.

In order to track the free interface of the melt pool and understand the evolution of the melt pool, the flow of fluid, and the interface behavior of gas and liquid, a physical model is developed by using the VOF method in this paper. Its characteristics are a combined heat source model, including a parabolic rotation and a cylindrical distribution, and a powder bed stochastic distributed model with powder particle size. The unit interface between the metallic and gas phase in the laser-powder interaction zone can only be loaded by the heat source. Only the first and second laser scanning tracks are simulated to reduce the calculation time. The simulation results show that process parameters such as laser power and scanning speed have significant effects on the fluid flow and surface morphology in the melt pool, which are in good agreement with the experimental results. Compared with the first track, the second track has larger melt pool geometry, higher melt temperature, and faster fluid flow. The melt flows intensely at the initial position due to the high flow rate in the limited melt space. Because there is enough space for the metal flow, the second track can obtain smooth surface morphology more easily compared to the first track. The melt pool temperature at the laser beam center fluctuates during the laser scanning process. This depends on the effects of the interaction between heat conduction or heat accumulation or the interaction between heat accumulation and violent fluid flow. The temperature distribution and fluid flow in the melt pool benefit the analysis and understanding of the evolution mechanism of the melt pool geometry and surface topography and further allow regulation of the L-PBF process of Ti6Al4V.

Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Purpose: We built a joint replacement loosening model based on the original rabbit model of infection and evaluated the performance characteristics of 18 F-FDG and 68  Ga-FAPI in evaluating infection and loosening., Methods: After surgery, the rabbits were divided into four groups, with six individuals in the control group and 10 each in the aseptic loosening, S. aureus and S. epidermidis groups. PET/CT and serological examination were performed three times at two-week intervals. After the rabbits were euthanized, micro-CT, tissue pathology, pullout tests and scanning electron microscopy (SEM) were performed., Results: The pullout test and SEM showed the feasibility of the aseptic loosening model. 18 F-FDG showed similar performance in the control and loosening groups. The SUVmax of the S. aureus group was consistently higher than that of the S. epidermidis group. As for 68  Ga-FAPI, the SUVmax of the control group was lowest in the second week and gradually increased over subsequent weeks. The SUVmax of the loosening group began to exceed that of the control group after the second week. The SUVmax of the S. aureus group in the second week was the lowest among the four groups and increased as the number of weeks increased. The pathology results showed concordance with the performance of PET/CT. Linear regressions between SUVmax and serology showed that 18 F-FDG was positively correlated with CRP and IL-6, while 68  Ga-FAPI revealed negative correlations with CRP and IL-6 in the second week and positive correlations in the sixth week. In addition, the SUVmax and MT(target)V of both 18 F-FDG and 68  Ga-FAPI were negatively correlated with bone volume/trabecular volume (TV) and bone surface area/TV., Conclusion: In this longitudinal observation, 68  Ga-FAPI showed greater sensitivity than 18 F-FDG in detecting diseases, and 68  Ga-FAPI had no intestinal or muscular uptake. The MT(target)V of 68  Ga-FAPI was larger than that of 18 F-FDG, which meant that 68  Ga-FAPI had the potential to define the scope of lesions more accurately. Finally, the SUVmax of 68  Ga-FAPI could not differentiate between loosening and infection; further study of the diagnostic criteria is warranted., (© 2022. The Author(s).)

Objective: Provide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors., Design and Methods: Single-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors., Results: A series of transcripts related to hormone processing peptidases and genes involved in the structural organization of secretory vesicles were reduced in silent compared to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited several features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the loss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features., Conclusions: Our findings provide novel insights into the mechanisms of impaired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcriptional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion.

Background: Spinal cord injury (SCI) is a devastating disease that lacks effective treatment. Interestingly, recent studies indicated that vagus nerve stimulation (VNS), neuromodulation that is widely used in a variety of central nervous system (CNS) diseases, improved motor function recovery after SCI. But the exact underlying mechanism of how VNS ameliorates SCI is unclear. This study aimed to confirm the efficacy and further explore the potential therapeutic mechanism of VNS in SCI., Method: A T10 spinal cord compression model was established in adult female Sprague-Dawley rats. Then the stimulation electrode was placed in the left cervical vagus nerve (forming Sham-VNS, VNS, and VNS-MLA groups). Basso-Beattie-Bresnahan (BBB) behavioral scores and Motor evoked potentials (MEPs) analysis were used to detect motor function. A combination of histological and molecular methods was used to clarify the relevant mechanism., Results: Compared with the Sham-VNS group, the VNS group exhibited better functional recovery, reduced scar formation (both glial and fibrotic scars), tissue damage, and dark neurons, but these beneficial effects of VNS were diminished after alpha 7 nicotinic acetylcholine receptor (α7nAchR) blockade. Specifically, VNS inhibited the pro-inflammatory factors TNF-α, IL-1β, and IL-6 and increased the expression of the anti-inflammatory factors IL-10. Furthermore, we found that VNS promotes the shift of M1-polarized Iba-1 + /CD86 + microglia to M2-polarized Iba-1 + /CD206 + microglia via upregulating α7nAchR to alleviate neuroinflammation after SCI., Conclusion: Our results demonstrated that VNS promotes microglial M2 polarization through upregulating α7nAChR to reduce neuroinflammation, thus improving motor function recovery after SCI. These findings indicate VNS might be a promising neuromodulation strategy for SCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Feng, Min, Deng, Tan, Hong, Gong, Zhang, Liu and Hou.)

Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Surveys based on western populations have identified many risk factors for dysphagia in older people, but the potential risk factors consistent with the demographic characteristics of older, hospitalized Chinese patients require further study. This single-center prospective study aimed to determine the incidence of dysphagia in western China, and to develop and validate a model to predict the risk of dysphagia among older patients. A total of 343 inpatients (aged ≥ 65 years without dysphagia and cognitive impairment) were included. A score ≥ 2 on the Eating Assessment Tool-10 was defined as dysphagia. After a six-month follow-up, 70 (20.4%) patients were found to have dysphagia. The final model included age, wearing dentures, activities of daily living, cerebral vascular disease, coronary heart disease, and malignancy. The developed model has high predictive accuracy and can be easily implemented in daily practice., Competing Interests: Declaration of Competing Interests The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Proinflammatory cytokines play a causal role in the development of hyperinsulinemia and T2MD. FOXO1, a transcription factor which is known to enhance proinflammation, was recently shown to be involved in obesity-induced β cell dysfunction. However, molecular mechanisms for the association remained elusive. In this study, we first found that both leptin (10 nM) and TNF- α (20 ng/ml) significantly inhibited glucose-stimulated insulin secretion (GSIS) of INS-1E cells. When in combination, the GSIS function of INS-1E cells was significantly increased compared with that of the leptin alone treatment, indicating that TNF- α attenuated the inhibiting effect of leptin on GSIS of INS-1E cells. Similarly, we found that TNF- α has the same inhibitory effect on leptin in regulating insulin synthesis and secretion, and the survival and apoptosis of insulin cells. Further studies showed that TNF- α blocks leptin pathway by reducing the expression of leptin receptor (LepRb, also called OBRb) and inhibiting the activation of STAT3, a key molecule involved in the leptin signaling pathway in INS-1E cells. Besides, the downregulated expression of phosphorylated FOXO1 was found to be involved in the possible mechanism of TNF- α . Overexpression of constitutively active FOXO1 markedly aggravated the LepRb reduction by TNF- α treatment of INS-1E cells, and the endogenous FOXO1 knockdown abolished the effect of TNF- α on INS-1E cells. Furthermore, we have proved that FOXO1 could directly bind to the promoter of LepRb as a negative transcription regulator. Taken together, the results of this study reveal that TNF- α -induced LepRb downregulated in pancreatic β cells and demonstrate that transcriptional reduction of FOXO1 might be the primary mechanism underlying TNF- α promoting INS-1E leptin resistance and β cell dysfunction. Conclusions . Our current studies based on INS-1E cells in vitro indicate that the inflammatory factor TNF- α plays an important role in the development of INS-1E leptin resistance and glucose metabolism disorders, probably through FOXO1-induced transcription reduction of LepRb promoter in pancreatic β cells, and FOXO1 may be a novel target for treating β cell dysfunction in obesity-induced hyperinsulinemia and T2DM., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Yang Zhang et al.)

Objectives: Myocardial I/R injury is one of the most serious complications after reperfusion therapy in patients with myocardial infarction. Remifentanil has been found to protect the heart against I/R injury. However, its underlying mechanism remains uncertain in myocardial I/R injury., Methods: The myocardial I/R injury rat model was established by 30 min of ischaemia followed by 24 h of reperfusion. The animal model was evaluated by the levels of TC, ALT and AST and H&E staining. The binding of miR-206-3p and TLR4 was predicted and verified using TargetScan software, luciferase reporter and RNA pull-down assays. The functional role and mechanism of remifentanil were identified by ultrasonic echocardiography, oxidative stress markers, H&E, Masson and TUNEL staining and western blot., Key Findings: The rat myocardial I/R injury model displayed a significantly high level of TC, ALT, AST, TLR4, p-IκBα and p-p65 and the presence of disorganized cells and inflammatory cell infiltration. The model also showed increased levels of LVEDD, LVESD, MDA, fibrosis and apoptosis and decreased levels of EF, FS, SOD and GSH, which were reversed with remifentanil treatment. Knockdown of miR-206-3p damaged cardiac function and aggravated oxidative stress. miR-206-3p could directly bind to TLR4. TLR4 overexpression destroyed cardiac function, exacerbated oxidative stress, increased levels of p-IκBα and p-p65 and aggravated pathology manifestation affected by remifentanil., Conclusions: Our results elucidated that remifentanil alleviated myocardial I/R injury by miR-206-3p/TLR4/NF-κB signalling axis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cashmere fineness is an important index to evaluate cashmere quality. Liaoning Cashmere Goat (LCG) has a large cashmere production and long cashmere fiber, but its fineness is not ideal. Therefore, it is important to find genes involved in cashmere fineness that can be used in future endeavors aiming to improve this phenotype. With the continuous advancement of research, the regulation of cashmere fineness has made new developments through high-throughput sequencing and genome-wide association analysis. It has been found that translatomics can identify genes associated with phenotypic traits. Through translatomic analysis, the skin tissue of LCG sample groups differing in cashmere fineness was sequenced by Ribo-seq. With these data, we identified 529 differentially expressed genes between the sample groups among the 27197 expressed genes. From these, 343 genes were upregulated in the fine LCG group in relation to the coarse LCG group, and 186 were downregulated in the same relationship. Through GO enrichment analysis and KEGG enrichment analysis of differential genes, the biological functions and pathways of differential genes can be found. In the GO enrichment analysis, 491 genes were significantly enriched, and the functional region was mainly in the extracellular region. In the KEGG enrichment analysis, the enrichment of the human papillomavirus infection pathway was seen the most. We found that the COL6A5 gene may affect cashmere fineness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Zhang, Xu, Qin, Gu, Cai, Bai, Zhang, Chen, Sun, Wu and Wang.)

Context: Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene., Objective: This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing disease (CD)., Methods: Next-generation sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the 3 NR3C1-mutant and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20), and GR protein expression was quantified by Western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription, and ACTH secretion were tested., Results: Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC scores than nonrecurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR., Conclusion: Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC. Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined. Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells. Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Liu, Yu, Zhang, Shi and Liang.)

Background: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models., Methods: To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures., Findings: scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months., Interpretation: Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD., Funding: This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma recurrence and metastasis after microwave ablation (MWA) are challenges in the clinic. This study showed that mannose-derived carbon dots (Man-CDs) could effectively capture several "danger signals" (DS) after MWA treatment and then deliver DS specifically to dendritic cells (DCs). This improved delivery of DS to DCs enhanced the processing and presentation of tumor-associated antigens by DCs. The results demonstrated that intratumoral injection of Man-CDs after MWA therapy elicited a potent tumor-specific immune response and finally led to the effective suppression of both primary and distant tumors. MWA + Man-CD treatment could efficiently reject tumor cell rechallenge in vivo . This study demonstrated that Man-CD nanoparticles are effective adjuvants that can improve MWA therapy by eliciting a tumor-specific immune response.

With the spread of COVID-19 in China at the beginning of 2020, MOOCs, as a kind of currently popular online learning resource, have played a dominant role in higher education field. However, chiefly focusing on teaching organization and learning process in MOOCs, previous studies have paid inadequate attention to lecturers' discourse. In order to provide some useful views on this issue, this study investigates EFL lecturers' metadiscourse in Chinese university MOOCs to sketch its distinctive pattern across course types. Based on a self-built corpus, this research adopted interpersonal model as theoretical foundation and analyzed the frequency and functions of metadiscourse by AntConc 3.5.7 and IBM SPSS 23. Findings suggest that specific educational context in MOOCs leads to low frequency of metadiscourse and its use is mainly aimed at the enhancement of intelligibility, reliability, and interactivity. Besides, course types with different knowledge structures also exert certain influence on metadiscourse usage. Course types focusing on procedural knowledge (i.e. the knowledge related to practical process) tend to apply metadiscourse to enhance intelligibility and interactivity, while the ones stressing declarative knowledge (i.e. the knowledge related to explicit facts) attach more importance to reliability. Lastly, the paper concludes with implications for EFL lecturers' metadiscourse in Chinese university MOOCs., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021.)

Context: Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth., Objective: To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth., Design: High throughput screen employing a novel "gain of signal" ACTH AlphaLISA assay., Setting: Academic medical center., Patients: Corticotroph tumor tissues from patients with CD., Interventions: None., Main Outcome Measures: Potent inhibitors of corticotroph tumor ACTH secretion and growth., Results: From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion., Conclusions: Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: The present study was designed to investigate the potential role and the mechanism of equilibrative nucleoside transporter 1 (ENT1) on neuronal apoptosis and neurological deficits after middle cerebral artery occlusion (MCAO) in rats., Methods: One hundred and thirty-four male Sprague-Dawley rats were subjected to two hours of MCAO followed by reperfusion. The time course of the expression level of ENT1 and phosphorylation of CREB were detected by western blot and immunofluorescence staining. Another set of animals were administrated with NBTI, the ENT1 inhibitor, by daily intraperitoneal injection starting at 0.5 h post-MCAO, infarction volume and neurological deficits were measured both at 24 h and 72 h post MCAO. We further explored the neuroprotection machenism by using H89, cAMP dependent protein kinase inhibitor, the expression of Bcl-2, Bax, phosphorylated CREB and Cleaved caspase-3 were quantified by Western blot, neuronal apoptosis were analyed by TUNEL staining., Results: The endogenous expression of ENT1 were significantly increased and peaked at 12 h after MCAO. High-dose of NBTI (15 mg/kg) reduced brain infarction volume and improved neurologic deficits both at 24 h and 72 h post MCAO. Moreover, NBTI significantly increased the level of CREB phosphorylation and extracellular adenosine concentration, and decreased the neuronal apoptosis 24 h after MCAO. NBTI treatment reduced the expression of Bax and cleaved caspase-3, while up-regulated Bcl-2 compared with vehicle group. These effects were abolished by H89 pretreatment., Conclusions: ENT1 inhibition prevented neuronal apoptosis and improves neurological deficits through cAMP/PKA/CREB/Bcl-2 signaling pathway after MCAO in rats. ENT1 might be an effective target in the treatment strategy for ischemic stroke., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in adaptive stress responses and maintaining organism homeostasis. The pituitary corticotroph is the central player in the HPA axis and is regulated by a plethora of hormonal and stress related factors that synergistically interact to activate and temper pro-opiomelanocortin (POMC) transcription, to either increase or decrease adrenocorticotropic hormone (ACTH) production and secretion as needed. Nuclear receptors are a family of highly conserved transcription factors that can also be induced by various physiologic signals, and they mediate their responses via multiple targets to regulate metabolism and homeostasis. In this review, we summarize the modulatory roles of nuclear receptors on pituitary corticotroph cell POMC transcription, describe the unique and complex role these factors play in hypothalamic-pituitary-adrenal axis (HPA) regulation and discuss potential therapeutic targets in disease states.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer, and the 5-year overall survival (OS) rate for HCC remains unsatisfying worldwide. Microwave ablation (MWA) is a minimally invasive therapy that has made progress in treating HCC. However, HCC recurrence remains problematic. Therefore, combination therapy may offer better outcomes and enhance MWA efficiency through improved tumor control. We have developed doxorubicin-loaded liposomes (DNPs) as an efficient nanoplatform to enhance MWA of hepatocellular carcinoma even at the mild ablation condition. In this study, we demonstrated that the uptake of DNPs by HCC cells was increased 1.5-fold compared with that of free DOX. Enhanced synergism was observed in the combination of DNPs and MWA, which induced nearly 80% cell death. The combination of mild MWA and DNPs enhanced the ablation efficiency of HCC with significant inhibition of liver tumors and accounted for the longest survival rate among all groups. A much higher accumulation of the DNPs was observed in the transitional zone than in the ablation zone. No apparent systemic toxicity was observed for any of the treatments after 14 days. The present work demonstrates that DNPs combined with MWA could be a promising nanoparticle-based therapeutic approach for the treatment of hepatocellular carcinoma and shows potential for future clinical applications., (Copyright © 2020 Wu, Zhang, Yu, Dou, Li, Mu and Liang.)

Our previous studies have demonstrated that XIAP promotes bladder cancer metastasis through upregulating RhoGDIβ/MMP-2 pathway. However, the molecular mechanisms leading to the XIAP upregulation was unclear. In current studies, we found that XIAP was overexpressed in human high grade BCs, high metastatic human BCs, and in mouse invasive BCs. Mechanistic studies indicated that XIAP overexpression in the highly metastatic T24T cells was due to increased mRNA stability of XIAP that was mediated by downregulated miR-200c. Moreover, the downregulated miR-200c was due to CREB inactivation, while miR-200c downregulation reduced its binding to the 3'-UTR region of XIAP mRNA. Collectively, our results demonstrate the molecular basis leading to XIAP overexpression and its crucial role in BC invasion.

This paper investigates the effect of porosity and unit cell size variation in topology optimized (TOP) and selective laser melting (SLM) fabricated Ti6Al4V lattice structure on the mechanical properties including compressive strength, failure mechanism and dynamic elastic modulus. Meanwhile, mathematical relations between mechanical properties and geometric parameters are obtained based on Gibson-Ashby model. The results show that both ultimate compressive strength (σ = 23∼498 MPa) and dynamic elastic modulus (E = 3.5∼55.47 GPa) of TOP lattice structures gradually decrease with the increase in porosity and unit cell size. The analysis combining experimental and numerical results indicates that TOP lattice structures are elastic-brittle porous material and have two failure mechanisms. The numerical predicted stress-strain curves are compared with the experimental ones. The numerical models incorporating the Johnson-Cook damage model could predict the slip direction of 45° failure band and ultimate compressive strength. Classical Gibson-Ashby model was used to predict the relation between relative density and mechanical properties of lattice structures. The exponential factors (n) of fitted models are obviously affected by unit cell size, which are determined by the number of unit cells in compressive test and SLM manufacturability in dynamic elastic modulus test. A 3D Modulus-Density-Unit Cell Size model is innovatively proposed, which can provide theoretical basis of tailoring orthopedic implant filled with functional gradient TOP lattice structures., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Published studies have investigated the prognostic roles of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in gastroesophageal cancer patients with the controversial results. The aim of the study was to systematically evaluate the impacts of ERα and ERβ on the overall survival (OS) in patients., Method: Relevant eligible studies were extracted from PubMed, Embase, Web of Science, CNKI and Wanfang databases (from the start date to November 2018) following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. HR (hazard ratio) with 95% confidence intervals (CIs) were used to assess the prognostic values of ERα and ERβ for OS in patients., Results: High ERα expression was associated with poor OS (HR = 1.58, 95% CI = 1.29-1.94, P < .001) and ERβ with better OS (HR = 0.56, 95% CI = 0.37-0.83, P = .004) in gastroesophageal cancer. Furthermore, unfavorable OS was found in Chinese gastroesophageal patients with higher ERα expression (HR = 1.57, 95% CI = 1.25-1.96, P < .001) and better OS with higher ERβ expression (HR = 0.51, 95% CI = 0.31-0.83, P < .01) in our subgroup analysis. Meanwhile, worse OS was found in esophageal squamous cell carcinoma (ESCC) patients with high ERα expression (HR = 1.74, 95% CI = 1.33-2.26, P < .001), and favorable OS in ESCC with ERβ overexpression (HR = 0.40, 95% CI = 0.31-0.52, P < .001). Besides, high ERα expression was associated with lower tumor differentiation in ESCC (OR = 1.64; 95% CI = 1.02-2.64, P = .04) and ERβ was linked with better tumor differentiation in gastric adenocarcinoma (GCA) (OR = 0.49; 95% CI = 0.26-0.94, P = .03)., Conclusions: ERα and ERβ might serve as potential prognostic biomarkers for gastroesophageal cancer patients. ERα overexpression predicted poor OS and lower tumor differentiation, and ERβ suggested favorable OS and better tumor differentiation. Further related studies should be performed to test these results.

PHLPP1 (PH domain and leucine rich repeat protein phosphatase 1) is a newly identified family of Ser/Thr phosphatases that catalyzes the dephosphorylation of a conserved regulatory motif of the AGC kinases resulting in a tumor suppressive function, while CDKN1B/p27 also acts as a tumor suppressor by regulating cell cycle, senescence, apoptosis, and cell motility. Our most recent studies reveal that CDKN1B is required for PHLPP1 abundance, which contributes to the inhibition of carcinogenic arsenite-induced cell malignant transformation through inhibition of RPS6-mediated Hif1a translation. However, nothing is known about the mechanisms underlying the crosstalk between these 2 key tumor suppressors in intact cells. Here, for the first time to the best of our knowledge, we show that CDKN1B is able to promote PHLPP1 protein translation by attenuating the abundance of Mir6981 , which binds directly to the 5'untranslated region (UTR) of Phlpp1 mRNA. Further studies indicate that the attenuation of Mir6981 expression is due to macroautophagy/autophagy-mediated degradation of Mir6981 in an SQSTM1/p62-dependent fashion. Moreover, we have determined that Sqstm1 is upregulated by CDKN1B at the level of transcription via enhancing SP1 protein stability in an HSP90-depdendent manner. Collectively, our studies prove that: 1) SQSTM1 is a CDKN1B downstream effector responsible for CDKN1B-mediated autophagy; 2) by promoting the autophagy-mediated degradation of Mir6981 , CDKN1B exerts a positive regulatory effect on PHLPP1 translation; 3) Mir6981 suppresses PHLPP1 translation by binding directly to its mRNA 5'-UTR, rather than classical binding to the 3'-UTR. These findings provide significant insight into understanding the crosstalk between CDKN1B and PHLPP1. Abbreviations: ATG: autophagy related; ACTB: actin beta; BAF: bafilomycin; BECN1: beclin 1; Cdkn1b / p27 : cyclin-dependent kinase inhibitor 1B; CHX: cycloheximide; DMEM: dulbecco's modified eagle medium; FBS: fetal bovine serum; GAPDH: glyceraldehyde -3-phosphate dehydrogenase; Hif1a : hypoxia inducible factor 1, alpha subunit; Hsp90 : heat shock protein 90; JUN: Jun proto-oncogene, AP1 transcription factor subunit; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MG132: proteasome inhibitor; Mtor : mechanistic target of rapamycin kinase; Phlpp1 : PH domain and leucine rich repeat protein phosphatase 1; Phlpp2 : PH domain and leucine rich repeat protein phosphatase 2; Pp2c : protein phosphatase 2 C; RPS6: ribosomal protein S6; Sp1 : trans-acting transcription factor 1; Sqstm1/p62 : sequestosome 1; TUBA: alpha tubulin; 3'-UTR; 3'-untranslated region; 5'-UTR: 5'-untranslated region.

A blue emitting phosphor Li 2 Sr 0.9 Mg 0.1 SiO 4 :Ce 3+ , with long persistence, was synthesized via a high-temperature solid phase method. According to the X-ray diffraction analysis result, the introduction of Mg 2+ and Ce 3+ ions has no influence on the structure of the host material. Typical 5d- 2 F 5/2 and 5d- 2 F 7/2 transitions of Ce 3+ ions were detected by PL spectra, which corresponded to the CIE chromaticity coordinates of x = 0.1584, y = 0.0338. An optimal doping concentration of Ce 3+ was determined as of 0.4 at%. Furthermore, the Li 2 Sr 0.9 Mg 0.1 SiO 4 :Ce 3+ phosphor showed a typical triple-exponential afterglow behavior when the UV source was switched off. The highest lifetime of the electrons within the material reached a value of 73.9 s. Thermal stimulated luminescence study indicated that the afterglow of Li 2 Sr 0.9 Mg 0.1 SiO 4 :Ce 3+ was due to the recombination of the electrons with holes released from the traps generated by the doping of Ce 3+ ions in the Li 2 Sr 0.9 Mg 0.1 SiO 4 host. The afterglow mechanism of Li 2 Sr 0.9 Mg 0.1 SiO 4 :Ce 3+ is illustrated and discussed in detail on the basis of the experimental results., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aim: This study aimed to develop indocyanine green- and doxorubicin-loaded liposomes (DILPs) as theranostic nanoplatform for the detection of hepatocellular carcinoma (HCC) and as an efficient chemotherapeutic to enhance microwave ablation. Materials & methods: DILPs were synthesized and thoroughly characterized. Biocompatibility, tumor uptake and accumulation, and synergistic ablation-chemotherapeutic efficiency were systematically explored in them. In addition, human HCC surgical samples were used to test the affinity of DILPs for HCC. Results: The combination of microwave ablation and DILPs enhanced the ablation efficiency of HCC with apparent tumor inhibition. DILPs exhibited excellent diagnostic ability and could detect 2.5-mm HCC lesions via optoacoustic tomography imaging. DILPs had better affinity for human HCC surgical samples compared with normal liver tissue. Conclusion: Theranostic DILPs could serve as promising nanoparticles for treatment and management of HCC in the clinic.

Objective: We evaluated tumor recurrence and regrowth rates following endoscopic transnasal transsphenoidal (TNTS) surgical removal in a consecutive series of clinically nonfunctioning pituitary adenomas (CNFTs)., Design: Retrospective chart review of clinical, biochemical, and sellar MRI findings in all TNTS surgeries in patients with CNFT, performed by a single surgeon, between 2008 and 2015 (n = 280)., Patients: Ninety-three patients met eligibility criteria, with complete clinical, biochemical, and imaging follow-up for a 3-year minimum., Results: Of 85 patients who were not irradiated, 3-month postsurgical MRI demonstrated no residual tumor in 58 of 85 (68.2%), equivocal findings in 12 of 85 (14.1%), and definite residual tumor in 15 of 85 (17.6%) patients. Six of 85 (7.1%) demonstrated tumor regrowth by 3 years, and 2 further patients demonstrated true tumor recurrence at 3 and 6 years after surgery, respectively, for a total recurrence rate of 9.4% (8 of 85). Eight of the 93 patients were irradiated between 3 months and 4 years after pituitary surgery. In 3 patients with tumor regrowth, 2 exhibited residual tumor and 1 had no residual findings at the 3-month postoperative imaging. Overall, Ki-67 labeling index or Knosp grading did not predict recurrence., Conclusion: Tumor recurrence at 3 years was low (1 of 58; 1.7%) if the 3-month postoperative MRI showed no residual tumor. The findings support a less frequent imaging schedule for this group. Patients with definite residual tumor visible at 3 months harbor the greatest risk for tumor growth, but regrowth does not occur in all patients (6 of 15; 40%)., (Copyright © 2019 Endocrine Society.)

Context: Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and cotreatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs., Patient, Intervention, and Results: We describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immunohistochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6 in the index patient's tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammosomatotroph tumor GH3 cells, we observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation., Conclusions: In summary, our findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits antiproliferative actions in vitro. We suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments., (Copyright © 2019 Endocrine Society.)

Context: Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results., Case Description: We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues., Conclusions: To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy., (Copyright © 2019 Endocrine Society.)

Neuroblastoma is a commonly encountered solid tumor in early childhood with high neuroplasticity, and differentiation therapy is hypothesized to lead to tumor mass shrinkage and/or symptom relief. CgA is a tissue specific protein restricted to the diffuse neuroendocrine system, and widely expressed in neuroblastomas. Using knockdown and knockout approaches to deplete CgA levels, we demonstrated that CgA loss inhibits SH-SY5Y cell proliferation and leads to a morphological shift with increased expression of Schwann and extracellular matrix specific molecules, and suppression of chromaffin features. We further confirmed the effects of CgA in a series of neuroblastoma cells with [BE(2)-M17 and IMR-32] and without (SK-N-SH) N-Myc amplification. We demonstrated that CgA depletion reduced IGF-II and IGFBP-2 expression, increased IGFBP-3 levels, and suppresses IGF downstream signaling as evidenced by reduced AKT/ERK pathway activation. This was further supported by an increased anti-proliferative effect of the ERK inhibitor in the CgA depleted cells. In an in vivo xenograft neuroblastoma model, CgA knockdown led to increased S-phenotypic marker expression at both protein and mRNA levels. Together these results suggest that CgA maintains IGF secretion and intracellular signaling to regulate proliferation and differentiation in neuroblastomas., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is crucial for potentially decreasing the mortality of this disease. Herein, it is discovered that autophagy-related gene 7 (ATG7) is remarkably overexpressed in human invasive BC tissues. The knockdown of ATG7 in human BC cells dramatically inhibits cancer cell invasion, revealing that ATG7 is a key player in regulating BC invasion. Mechanistic studies indicate that MIR190A is responsible for ATG7 mRNA stability and protein overexpression by directly binding to ATG7 mRNA 3'-UTR. Furthermore, ATG7-mediated autophagy promotes HNRNPD (ARE/poly(U)-binding/degradation factor 1) protein degradation, and in turn reduces HNRNPD interaction with ARHGDIB mRNA, resulting in the elevation of ARHGDIB mRNA stability, and subsequently leading to BC cell invasion. The identification of the MIR190A/ATG7 autophagic mechanism regulation of HNRNPD/ARHGDIB expression provides an important insight into understanding the nature of BC invasion and suggests that autophagy may represent a potential therapeutic strategy for the treatment of human BC patients., Competing Interests: The authors declare no conflict of interest.

Li 1.27 Cr 0.2 Mn 0.53 O₂ layered cathodic materials were prepared by a nanomilling-assisted solid-state process. Whole-pattern refinement of X-ray diffraction (XRD) data revealed that the samples are solid solutions with layered α-NaFeO₂ structure. SEM observation of the prepared powder displayed a mesoporous nature composed of tiny primary particles in nanoscale. X-ray photoelectron spectroscopy (XPS) studies on the cycled electrodes confirmed that triple-electron-process of the Cr 3+ /Cr 6+ redox pair, not the two-electron-process of Mn redox pair, dominants the electrochemical process within the cathode material. Capacity test for the sample revealed an initial discharge capacity of 195.2 mAh·g -1 at 0.1 C, with capacity retention of 95.1% after 100 cycles. EIS investigation suggested that the high Li ion diffusion coefficient (3.89 × 10 -10 ·cm²·s -1 ), caused by the mesoporous nature of the cathode powder, could be regarded as the important factor for the excellent performance of the Li 1.27 Cr 0.2 Mn 0.53 O₂ layered material. The results demonstrated that the cathode material prepared by our approach is a good candidate for lithium-ion batteries.

Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a tumor suppressor that catalyzes the de-phosphorylation of the AGC kinases, while p27 acts as a tumor suppressor that regulates cell cycle, apoptosis, and cell motility. Our previous studies have identified that PHLPP2 participates in inhibition of transformation of human bronchial epithelial cells following lung carcinogen B[a]P/B[a]PDE exposure. However, nothing was known about the association of p27 with regulation of PHLPP2 expression and the role of PHLPP2 in bladder cancer (BC) invasion. In our current studies, we demonstrated that PHLPP2 inhibited BC invasion through promoting MMP2 degradation via p62-mediated autophagy; and p27 expression was able to stabilize PHLPP2 protein by inhibiting protein degradation of Hsp90, which could directly bind to PHLPP2 and protect it from degradation. More in-depth studies discovered that stabilization of Hsp90 by p27 was mediated by calpain1 proteolysis system, whereas p27 inhibited calpain1 gene transcription by attenuating Jak1/Stat1 cascade in human invasive BC cells. Collectively, we for the first time revealed PHLPP2 downregulation in BCs and its participating in promotion of BC invasion, as well as novel role of p27 and mechanisms underlying its regulation of PHLPP2 protein degradation through Hsp90-dependent manner. Our findings improve our understanding of p27 and PHLPP2 roles and their crosstalk in regulation of BC invasion, which further contributes to improve the current strategy for invasive bladder cancer therapy.

Neuroendocrine tumors, including carcinoids, are rare and insidiously growing tumors. Related to their site of origin, tumors can be functional, causing various forms of the carcinoid syndrome, owing to the overproduction of serotonin, histamine, or other bioactive substances. They often invade adjacent structures or metastasize to the liver and elsewhere. Treatment includes multimodal approaches, including cytoreductive surgery, locoregional embolization, cytotoxic therapy, peptide receptor radionuclide therapy, and various targeted therapies with goals of symptom relief and control of tumor growth. This article summarizes current and emerging approaches to management and reviews several promising future therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

It's well documented that over-production of reactive oxygen species (ROS) causes detrimental damages to cells. While a low level of ROS, such as H 2 O 2 , functions as signaling transducer and motivates cell proliferation in both cancer and non-transformed stem cells. As a double-edged sword, the direct evidence for demonstrating the function of H 2 O 2 in the cause of tumor is barely characterized in intact cells. In our current study, we found that targeted expression of mitochondrial catalase (mCAT), but not catalase, could significantly reduce the accumulation of H 2 O 2 in mouse epithelial JB6 Cl41 cells, consequently led to the cell malignant transformation and anchorage-independent cell growth. Further study revealed that this reduction of H 2 O 2 resulted in the translocation of nucleolin from the cytoplasm to nuclear, and maintaining the nucleolin nuclear location status, and in turn stabilizing the cox-2 mRNA and consequently leading to a COX-2 protein upregulation, as well as malignant transforming mCAT-overexpressed Cl41 cells. Collectively, our studies here provide direct experimental evidence demonstrating a novel function and molecular mechanisms of mCAT in transforming mouse Cl41 cells, and high significance insight into understanding the beneficial aspect of H 2 O 2 in circumventing tumor promotion and the theoretical basis for the management of H 2 O 2 in the clinic implementation as a chemotherapeutic strategy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The combination of topology optimization (TOP) and selective laser melting (SLM) provides the possibility of fabricating the complex, lightweight and high performance geometries overcoming the traditional manufacturing "bottleneck". This paper evaluates the biomechanical properties of porous structures with porosity from 40% to 80% and unit cell size from 2 to 8 mm, which are designed by TOP and manufactured by SLM. During manufacturability exploration, three typical structures including spiral structure, arched bridge structure and structures with thin walls and small holes are abstracted and investigated, analyzing their manufacturing limits and forming reason. The property tests show that dynamic elastic modulus and compressive strength of porous structures decreases with increases of porosity (constant unit cell size) or unit cell size (constant porosity). Based on the Gibson-Ashby model, three failure models are proposed to describe their compressive behavior, and the structural parameter λ is used to evaluate the stability of the porous structure. Finally, a numerical model for the correlation between porous structural parameters (unit cell size and porosity) and elastic modulus is established, which provides a theoretical reference for matching the elastic modulus of human bones from different age, gender and skeletal sites during innovative medical implant design and manufacturing., Competing Interests: The authors declare no conflict of interest.

Pre-menopausal female patients have a prolonged survival than post-menopausal patients, indicating that estrogen and/or estrogen receptor (ER) may have some biological effects on prognosis. ER expression in cancer tissue has been reported to be a significant prognostic marker in multiple human cancers. However, the prognostic value of estrogen and/or ER on female patients with esophageal squamous cell carcinoma (ESCC) is rarely reported. The present study was undertaken to elucidate the associations of serum estradiol level, tissue estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) expression with clinical response and reproductive factor changes in 387 female ESCC patients. Radioimmunoassay revealed that serum estradiol level was higher in pre-menopausal than those in peri-menopausal and post-menopausal patients. Furthermore, patients with higher serum estradiol level appeared to have a better survival. Immunostaining results suggested that ERα positive (+) expression was mainly located in cytoplasm of tumor cells with a positive rate of 69.9% and ERβ (+) was mainly located in nucleus of tumor cells with a positive rate of 64.9%. We did not find the relations of ER expression with tumor invasion (P>0.05), lymph node metastasis (P>0.05), TNM staging (P>0.05) and treatment method (P>0.05). Surprisingly, ERα (+) expression was higher in post-menopausal patients than those in pre-menopausal patients (P<0.05). Patients with number of pregnancy≥4 have a higher ERβ (+) expression than those patients with≤3 (P<0.05). Univariate and multivariate survival analysis showed that ERβ (+) expression in addition to ERα (-) expression are favorable prognostic markers in female ESCC patients (P<0.05). Further related study is needed to in-depth explore the potential mechanisms of ERα and ERβ in survival of female patients with ESCC., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)