Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

Downregulation of N4-acetylcytidine modification in myeloid cells attenuates immunotherapy and exacerbates hepatocellular carcinoma progression.

BACKGROUND: N4-acetylcytidine (ac4C) is a conserved and abundant mRNA modification that controls protein expression by affecting translation efficiency and mRNA stability. Whether the ac4C modification of mRNA regulates hepatocellular carcinoma (HCC) development or affects the immunotherapy of HCC is unknown. METHODS: By constructing an orthotopic transplantation mouse HCC model and isolating tumour-infiltrated immunocytes, we evaluated the ac4C modification intensity using flow cytometry. Remodelin hydrobromide (REM), an ac4C modification inhibitor, was systematically used to understand the extensive role of ac4C modification in immunocyte phenotypes. Single-cell RNA-seq was performed to comprehensively evaluate the changes in the tumour-infiltrating immunocytes and identify targeted cell clusters. RNA-seq and RIP-seq analyses were performed to elucidate the underlying molecular mechanisms. Tyramide Signal Amplification (TSA) analysis on the HCC tissue microarray was performed to explore the clinical relatedness of our findings. RESULTS: Ac4C modification promoted M1 macrophage infiltration and reduced myeloid-derived suppressor cell MDSCs infiltration in HCC. The inhibition of ac4C modification induces PDL1 expression by stabilising mRNA in the myeloid cells, thereby attenuating the CTL-mediated tumour cell-killing ability. High infiltration of ac4C+CD11b+ cells is positively related to a better prognosis in patients with HCC. CONCLUSIONS: Ac4C modification of myeloid cells enhanced the HCC immunotherapy by suppressing PDL1 expression.

Maternal Dietary Cholesterol and Egg Intake during Pregnancy and Large-for-Gestational-Age Infants: A Prospective Cohort Study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversy over whether pregnant females should limit their cholesterol intake. OBJECTIVES: The objective of this study was to investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4146 mother-child pairs were included based on the Jiangsu Birth Cohort study. Maternal dietary information was assessed with a semiquantitative food-frequency questionnaire. Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase in birth weight z-score, with per standard deviation increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 [95% confidence interval (CI): 0.07, 0.25] and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters was positively linked to LGA, with an adjusted relative risk of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared with mothers consuming ≤7 eggs/wk in the third trimester, the adjusted relative risk for having an LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/wk and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/wk (P-trend = 0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/wk during pregnancy, displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration.

BACKGROUND: The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. METHODS: The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). RESULTS: Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. CONCLUSION: Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function.

Analysis of the Prognostic and Immunological Role of HSPB1 in Pituitary Adenoma: A Potential Target for Therapy.

Background and Objectives: The diagnosis and treatment of pituitary adenomas with cavernous sinus invasion pose significant challenges for clinicians. The objective of this study is to investigate the expression profile and prognostic value of HSPB1 (heat shock protein beta-1) in pituitary adenomas with invasive and non-invasive features. Additionally, we aim to explore the potential relationship between HSPB1 expression and immunological functions in pituitary adenoma. Materials and Methods: A total of 159 pituitary adenoma specimens (73 invasive tumours and 86 non-invasive tumours) underwent whole-transcriptome sequencing. Differentially expressed genes and pathways in invasive and non-invasive tumours were analysed. HSPB1 was subjected to adequate bioinformatics analysis using various databases such as TIMER, Xiantao and TISIDB. We investigated the correlation between HSPB1 expression and immune infiltration in cancers and predicted the target drug of HSPB1 using the TISIDB database. Results: HSPB1 expression was upregulated in invasive pituitary adenomas and affected immune cell infiltration. HSPB1 was significantly highly expressed in most tumours compared to normal tissues. High expression of HSPB1 was significantly associated with poorer overall survival. HSPB1 was involved in the regulation of the immune system in most cancers. The drugs DB11638, DB06094 and DB12695 could act as inhibitors of HSPB1. Conclusions: HSPB1 may serve as an important marker for invasive pituitary adenomas and promote tumour progression by modulating the immune system. Inhibitors of HSPB1 expression are currently available, making it a potential target for therapy in invasive pituitary adenoma.

Catalytic divergent synthesis of imidazoles via reaction condition-dependent [3 + 2] cyclization of TosMIC.

A base-catalyzed divergent synthesis of multisubstituted imidazoles through TosMIC-based [3 + 2] cyclization reaction has been developed. In the presence of ketenimines and tBuONa, 1,4,5-trisubstituted imidazoles were obtained. Nonetheless, in the absence of ketenimines, 1,4-disubstituted imidazole was produced through cyclodimerization of TosMIC.

Therapeutic apheresis in kidney diseases: an updated review.

Besides conventional medical therapies, therapeutic apheresis has become an important adjunctive or alternative therapeutic option to immunosuppressive agents for primary or secondary kidney diseases and kidney transplantation. The available therapeutic apheresis techniques used in kidney diseases, including plasma exchange, double-filtration plasmapheresis, immunoadsorption, and low-density lipoprotein apheresis. Plasma exchange is still the leading extracorporeal therapy. Recently, growing evidence supports the potential benefits of double-filtration plasmapheresis and immunoadsorption for more specific and effective clearance of pathogenic antibodies with fewer side effects. However, more randomized controlled trials are still needed. Low-density lipoprotein apheresis is also an important supplementary therapy used in patients with recurrent focal segmental glomerulosclerosis. This review collects the latest evidence from recent studies, focuses on the specific advantages and disadvantages of these techniques, and compares the discrepancy among them to determine the optimal therapeutic regimens for certain kidney diseases.

Recent Advances in the Emerging Therapeutic Strategies for Diabetic Kidney Diseases.

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin-angiotensin-aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium-glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD.

The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas.

Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2ß (EIF2ß) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2ß in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2ß was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2ß and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2ß was greater than that in patients with a low EIF2ß (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2ß changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.

A Universal Biofilm Reactor Sensor for the Determination of Biochemical Oxygen Demand of Different Water Areas.

In this study, we developed a simple strategy to prepare a biofilm reactor (BFR) sensor for the universal biochemical oxygen demand (BOD) determination. The microorganisms in fresh water were domesticated by artificial seawater with different salinity gradients successively to prepare the BFR sensor. The prepared BFR sensor exhibits an efficient ability to degrade a variety of organic substances. The linear range of BOD determination by the BFR sensor is 1.0-10.0 mg/L-1 with a correlation coefficient of 0.9951. The detection limit is 0.30 mg/L according to three times of signal-to-noise ratio. What is more, the BFR sensor displayed excellent performances for the BOD determination of different water samples, including both fresh water and seawater. The 16S-rRNA gene sequencing technology was used to analyze the microbial species before and after the domestication. The results show that it is a general approach for the rapid BOD determination in different water samples.

PAM4 rolling-shutter demodulation using a pixel-per-symbol labeling neural network for optical camera communications.

The typical optical camera communication (OCC) modulation scheme is based on binary intensity modulation. To increase the transmission data rate, multi-level modulation format is highly desirable. In this work, we bring forward and demonstrate a rolling shutter 4-level pulse amplitude modulation (PAM4) demodulation scheme for OCC systems using pixel-per-symbol labeling neural network (PPSL-NN) for the first time up to the authors' knowledge. A bit-rate distance product of 28.8 kbit/s • m per color is achieved. The proposed scheme is to calculate and re-sample the pixel-per-symbol (PPS) to make sure the same number of pixels in each PAM4 symbol is corresponding to a label for the neural network. Experiment results reveal that the proposed scheme can efficiently demodulate high speed PAM4 signal in the rolling shutter OCC pattern.

Employing DIALux to relieve machine-learning training data collection when designing indoor positioning systems.

We propose and demonstrate using the DIALux software with our proposed linear-regression machine-learning (LRML) algorithm for designing a practical indoor visible light positioning (VLP) system. Experimental results reveal that the average position errors and error distributions of the model trained via the DIALux simulation and trained via the experimental data match with each other. This implies that the training data can be generated in DIALux if the room dimensions and LED luminary parameters are available. The proposed scheme could relieve the burden of training data collection in VLP systems.

Rolling-shutter-effect camera-based visible light communication using RGB channel separation and an artificial neural network.

We propose and demonstrate a light-panel and rolling-shutter-effect (RSE) camera-based visible light communication (VLC) system using Z-score normalization, red/green/blue (RGB) color channel separation, and 1-D artificial neural network (ANN). The proposed scheme can mitigate the high inter-symbol interference (ISI) generated by the RSE pattern due to the low pixel-per-bit and high noise-ratio (NR) of the display contents.

CMOS camera based visible light communication (VLC) using grayscale value distribution and machine learning algorithm.

We demonstrate a visible light communication (VLC) system using light emitting diode (LED) backlight display panel and mobile-phone complementary-metal-oxide-semiconductor (CMOS) camera. The panel is primarily used for displaying advertisements. By modulating its backlight, dynamic contents (i.e. secondary information) can be transmitted wirelessly to users based on rolling shutter effect (RSE) of the CMOS camera. As different display content will be displayed on the panel, the VLC performance is significantly limited if the noise-ratio (NR) is too high. Here, we propose and demonstrate a CMOS RSE pattern demodulation scheme using grayscale value distribution (GVD) and machine learning algorithm (MLA) to significantly enhance the demodulation.

Titania-Samarium-Manganese Composite Oxide for the Low-Temperature Selective Catalytic Reduction of NO with NH3.

A novel Ti-doped Sm-Mn mixed oxide (TiSmMnOx) was first designed for the selective catalytic reduction (SCR) of NOx with NH3 at a low temperature. The TiSmMnOx catalyst exhibited a superior catalytic performance, in which NOx conversion higher than 80% and N2 selectivity above 90% could be achieved in a wide-operating temperature window (60-225 °C). Specially, the catalyst also showed high durability against the large space velocity and excellent SO2/H2O resistance. Ti incorporation can efficiently inhibit MnOx crystallization and tune the MnOx phase during calcination at a high temperature. Subsequently, a high specific surface area as well as an increased amount of acid sites on the TiSmMnOx catalysts were produced. Further, the reducibility of the Sm-doped MnOx catalyst was modulated, facilitating NO oxidation and inhibiting NH3 nonselective oxidation. Consequently, a superior SCR activity was achieved at a low temperature and the operating temperature window of the TiSmMnOx catalyst was significantly widened. These findings may provide new insights into the reasonable design and development of the new non-vanadium catalysts with a high NH3-SCR activity for industrial application.

Using logistic regression classification for mitigating high noise-ratio advisement light-panel in rolling-shutter based visible light communications.

We propose and experimentally demonstrated a light-panel and image sensor based visible light communication (VLC) system using machine learning (ML) algorithm. The ML algorithm is compared with the traditional demodulation scheme and the experimental results show that even at very high noise-ratio (NR) light-panel display content, the proposed ML algorithm shows significant bit error rate (BER) improvement.

An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor.

We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation Kd is estimated to be ∼0.9 µM with a slow dissociation rate (t1/2 ∼ 15 min). X-ray structures of M2PYK complexes with alanine, phenylalanine, and tryptophan show the M2PYK locked in an inactive T-state conformation, while activators lock the M2PYK tetramer in the active R-state conformation. Amino-acid binding in the allosteric pocket triggers rigid body rotations (11°) stabilising either T or R states. The opposing inhibitory and activating effects of the non-essential amino acids serine and alanine suggest that M2PYK could act as a rapid-response nutrient sensor to rebalance cellular metabolism. This competition at a single allosteric site between activators and inhibitors provides a novel regulatory mechanism by which M2PYK activity is finely tuned by the relative (but not absolute) concentrations of activator and inhibitor amino acids. Such 'allostatic' regulation may be important in metabolic reprogramming and influencing cell fate.

Mitigation of performance degradation due to dynamic display contents in visible light communication using TV backlight and CMOS image sensor.

Here, we propose and demonstrate a performance degradation mitigation scheme in TV backlight and smart-phone-based visible light communication (VLC) system when the display content in the light-panel is dynamically changing. In order to evaluate the influence of the dynamic display contents to the VLC performance, we use a noise-ratio (NR) and noise-ratio standard deviation (NRSD) as the figure-of-merits for the bright-and-dark contrast of the display content; and the dispersal of the changing display content regarding the bright-and-dark contrast respectively. Performances of 4 dynamic display contents with different combinations of NR and NRSD are analyzed. They are: low NR and low NRSD (NR = 36.69%; NRSD = 0.0226); low NR and high NRSD (NR = 30.09%; NRSD = 0.2698); high NR and low NRSD (NR = 81.66%; NRSD = 0.0052); high NR and high NRSD (NR = 73.91%; and NRSD = 0.2717). The proposed scheme can work well; that is, even the transmission distance is up to 200 cm in both smart-phones. If the proposed scheme is not used, then high success rate can be observed only at the low NR and low NRSD display content when the transmission distance is < 100 cm.

Using advertisement light-panel and CMOS image sensor with frequency-shift-keying for visible light communication.

A frequency-shift-keying (FSK) visible light communication (VLC) system is proposed and demonstrated using advertisement light-panel as transmitter and mobile-phone image sensor as receiver. The developed application program (APP) in mobile-phone can retrieve the rolling shutter effect (RSE) pattern produced by the FSK VLC signal effectively. Here, we also define noise-ratio value (NRV) to evaluate the contrast of different advertisements displayed on the light-panel. Both mobile-phones under test can achieve success rate > 96% even when the transmission distance is up to 200 cm and the NRVs are low.

Forbidden Backscattering and Resistance Dip in the Quantum Limit as a Signature for Topological Insulators.

Identifying topological insulators and semimetals often focuses on their surface states, using spectroscopic methods such as angle-resolved photoemission spectroscopy or scanning tunneling microscopy. In contrast, studying the topological properties of topological insulators from their bulk-state transport is more accessible in most labs but seldom addressed. We show that, in the quantum limit of a topological insulator, the backscattering between the only two states on the Fermi surface of the lowest Landau band can be forbidden at a critical magnetic field. The conductivity is determined solely by the backscattering between the two states, leading to a resistance dip that may serve as a signature for topological insulator phases. More importantly, this forbidden backscattering mechanism for the resistance dip is irrelevant to details of disorder scattering. Our theory can be applied to revisit the experiments on Pb_{1-x}Sn_{x}Se, ZrTe_{5}, and Ag_{2}Te families, and will be particularly useful for controversial small-gap materials at the boundary between topological and normal insulators.