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1.
J Transl Med ; 22(1): 241, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443917

RESUMO

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.


Assuntos
Antígenos de Grupos Sanguíneos , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Checkpoint Imunológico , Ciclo-Oxigenase 2 , Dinoprostona , Inibidores de Ciclo-Oxigenase 2 , Inflamação , Receptores de Antígenos de Linfócitos T
2.
J Transl Med ; 22(1): 271, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38475831

RESUMO

BACKGROUND: Patients with spondyloarthritis (SpA)/HLA-B27-associated acute anterior uveitis (AAU) experience recurring acute flares, which pose significant visual and financial challenges. Despite established links between SpA and HLA-B27-associated AAU, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment. METHODS: To investigate the acute pathogenesis of SpA/HLA-B27-associated AAU, Mendelian randomization (MR) and single-cell transcriptomic analyses were employed. The MR incorporated publicly available protein quantitative trait locus data from previous studies, along with genome-wide association study data from public databases. Causal relationships between plasma proteins and anterior uveitis were assessed using two-sample MR. Additionally, colocalization analysis was performed using Bayesian colocalization. Single-cell transcriptome analysis utilized the anterior uveitis dataset from the Gene Expression Omnibus (GEO) database. Dimensionality reduction, clustering, transcription factor analysis, pseudotime analysis, and cell communication analysis were subsequently conducted to explore the underlying mechanisms involved. RESULTS: Mendelian randomization analysis revealed that circulating levels of AIF1 and VARS were significantly associated with a reduced risk of developing SpA/HLA-B27-associated AAU, with AIF1 showing a robust correlation with anterior uveitis onset. Colocalization analysis supported these findings. Single-cell transcriptome analysis showed predominant AIF1 expression in myeloid cells, which was notably lower in the HLA-B27-positive group. Pseudotime analysis revealed dendritic cell terminal positions in differentiation branches, accompanied by gradual decreases in AIF1 expression. Based on cell communication analysis, CD141+CLEC9A+ classic dendritic cells (cDCs) and the APP pathway play crucial roles in cellular communication in the Spa/HLA-B27 group. CONCLUSIONS: AIF1 is essential for the pathogenesis of SpA/HLA-B27-associated AAU. Myeloid cell differentiation into DCs and decreased AIF1 levels are also pivotal in this process.


Assuntos
Espondilartrite , Uveíte Anterior , Humanos , Doença Aguda , Teorema de Bayes , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Espondilartrite/genética , Espondilartrite/metabolismo , Uveíte Anterior/genética , Uveíte Anterior/metabolismo
3.
Adv Mater ; 36(16): e2312334, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38236142

RESUMO

Alternating current (AC)-driven quantum-dot light-emitting diodes (QLEDs) are superior to direct current-driven QLEDs because they can be directly integrated into household AC electricity and have high stability. However, achieving high-performance AC-driven QLEDs remains challenging. In this work, a bipolar QLED with coplanar electrodes is realized by horizontally connecting a regular QLED and an inverted QLED in series using an Al bridging layer. The bipolar QLED can be turned on with either a positive or a negative bias voltage, with a high external quantum efficiency (EQE) of 22.9%. By replacing the Al with Ag, the resistances of the electron transport layers are effectively reduced, and thus the bipolar QLED shows an enhanced brightness of 16370 cd m-2 at 15 V. By connecting multiple bipolar QLEDs in series, the resulting light source can be directly driven by a 220 V/50 Hz household power supply without the need for back-end electronics. The bipolar QLED can also be realized by vertically stacking a regular QLED and an inverted QLED with a metallic intermediate connection layer. It is demonstrated that the coplanar or vertical bipolar QLEDs could find potential applications in household AC electricity play-and-plug solid-state lighting and single- or double-sided displays.

4.
Adv Mater ; 36(7): e2309123, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38038258

RESUMO

The poor stability of blue quantum-dot (QD) light-emitting diodes (B-QLEDs) hinders their application in displays. To improve the stability of B-QLEDs, the degradation mechanism should be revealed. Here, the degradation mechanism of B-QLEDs is investigated by monitoring the changes occurring in the QDs and the hole transport layers (HTL) during device operation, respectively. It is revealed that the accumulation of electrons within the QDs is responsible for the degradation of the devices. On the one hand, the accumulated electrons induce the detachment of oleic acid ligands, leading to permanent damage to the stability of B-QDs. On the other hand, the accumulated electrons leak into the HTL or recombine at the HTL/QDs interface, leading to the degradation of HTL. The formation of surface defects in B-QDs and the decomposition of HTL contribute to the degradation of B-QLEDs. The results reveal the strong dependence of B-QLEDs stability on the accumulated electrons, the QDs and the HTL, which can help researchers to develop effective design strategies for improving the lifespan of B-QLEDs.

5.
Small Methods ; 8(2): e2300359, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37357153

RESUMO

Light-emitting diodes (LEDs) based on colloidal quantum-dots (QDs) such as CdSe, InP, and ZnSeTe feature a unique advantage of narrow emission linewidth of ≈20 nm, which can produce highly accurate colors, making them a highly promising technology for the realization of displays with Rec. 2020 color gamut. With the rapid development in the past decades, the performances of red and green QLEDs have been remarkably improved, and their efficiency and lifetime can almost meet industrial requirements. However, the industrialization of QLED displays still faces many challenges; for example, (1) the device mechanisms including the charge injection/transport/leakage, exciton quenching, and device degradation are still unclear, which fundamentally limit QLED performance improvement; (2) the blue performances including the efficiency, chromaticity, and stability are relatively low, which are still far from the requirements of practical applications; (3) the color patterning processes including the ink-jet printing, transfer printing, and photolithography are still immature, which restrict the manufacturing of high resolution full-color QLED displays. Here, the recent advancements attempting to address the above challenges of QLED displays are specifically reviewed. After a brief overview of QLED development history, device structure/principle, and performances, the main focus is to investigate the recent discoveries on device mechanisms with an emphasis on device degradation. Then recent progress is introduced in blue QLEDs and color patterning. Finally, the opportunities, challenges, solutions, and future research directions of QLED displays are summarized.

6.
J Am Chem Soc ; 146(1): 24-32, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37830927

RESUMO

Developing new strategies to enable chemo- and regioselective reductions is an important topic in chemical research. Herein, an efficient and regioselective Pd/IPrBIDEA-catalyzed ring-opening hydrodefluorination of gem-difluorocyclopropanes to access terminal fluoroalkenes is developed. The success of this transformation was attributed to the use of 3,3-dimethylallyl Bpin as a novel hydride donor. DFT calculations suggest that a direct 3,4'-hydride transfer via a 9-membered cyclic transition state is more favorable, which combined with the irreversibility of the reaction enables the unusual selectivity for the less thermodynamically stable terminal alkene isomer. This reaction mode is also applicable to a variety of regioselective allylic and propargyl reductions.

7.
J Am Chem Soc ; 145(50): 27254-27261, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38078874

RESUMO

Alkene borylfunctionalization reactions have emerged as useful methods for chemical synthesis. While much progress has been made on 1,2-borylamination reactions, the related 1,1- and 1,3-borylaminations have not been reported. Herein, a Ni-catalyzed 1,1-borylamination of 1,1-disubstituted and monosubstituted alkenes and a 1,3-borylamination of cyclic alkenes are presented. Key to development of these reactions was the identification of an alkyllithium activator in combination with Mg salts. The utility of the products and the mechanistic details are discussed.

8.
Cell Death Discov ; 9(1): 450, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38086844

RESUMO

Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata, is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.

9.
Digit Health ; 9: 20552076231220791, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38107978

RESUMO

Introduction: Diabetic foot self-management intervention programs have been proven to positively influence individuals' behaviors in preventing diabetic foot ulcers. Using digital technologies to deliver programs can facilitate compliance with diabetes self-management programs. However, few studies have focused on the effects of such digital programs on improving the self-efficacy and behaviors of older adults with type 2 diabetes in the community. Aim: To evaluate the effects of a digital foot self-management program on self-efficacy, self-care behavior, and Hemoglobin A1c levels. Design: A single-blinded, randomized controlled trial was conducted. Methods: The intervention program comprised a 4-week digital foot care program with one face-to-face education session, phone calls once weekly, and LINE messages (social media) three times per research nurse and a follow-up of three months. Patients in the control group received routine care. Results: A total of 100 participants (n = 50 in the control and n = 50 in the intervention groups) completed the study with a mean age of 67.55 (SD = 11.17). The results showed significant improvements in self-efficacy (F = 2187.24, p < 0.01) and self-care behavior (F = 614.71, p < 0.01) in foot care between the groups. The Hemoglobin A1c levels showed a 0.41% reduction over time in the experimental group (t = -3.759; p < 0.01), whereas the control group showed a 0.06% reduction (t = -0.797, p > 0.05). Conclusion: The newly developed digital foot self-management program was effective in community-dwelling older adult patients with type 2 diabetes.

10.
Nat Commun ; 14(1): 8308, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38097583

RESUMO

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.


Assuntos
Canais de Cloreto , Receptores de GABA-A , Animais , Picrotoxina/farmacologia , Picrotoxina/química , Canais de Cloreto/metabolismo , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Dieldrin/química , Metilação , Mamíferos/metabolismo
11.
Hu Li Za Zhi ; 70(6): 36-47, 2023 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-37981882

RESUMO

BACKGROUND: Motivation is an important factor in disease management for diabetic patients. However, motivational strengthening interventions have been inadequately effective in effecting behavior change in this group. PURPOSE: This study was designed to investigate the effect of a motivational interview intervention on self-efficacy, self-care behavior, and blood sugar control in patients with type 2 diabetes. METHODS: The target population comprised patients with type 2 diabetes in two medical wards of a regional hospital in the southern Taiwan. The 112 participants were randomly assigned to the experimental group (n = 56) and control group (n = 56). Over a three month period, the experimental group received 6 motivational interview sessions of 50 minutes each in addition to usual diabetes care, while the control group received usual diabetes care on the ward. Both groups completed the demographic questionnaire, Chinese version of Diabetes Self-Efficacy Scale, Diabetes Self-Care Behavior Scale, glycosylated hemoglobin level pre-test, and 3 months post-test survey. The results were analyzed using SPSS 22.0 for Windows. RESULTS: A total of 55 patients in the experimental group and 52 patients in the control group completed the study. After analysis, significant inter-group differences in self-efficacy and self-care behavior were found between the experimental group and the control group at pre-test and three-month post-test (p < .001). For the experimental group, the three-month post-test score and glycated hemoglobin value were higher than at pre-test. The three-month post-test value was significantly lower (p < .001) than the pre-test value, and the change effect in the experimental group was better than that in the control group. There was a significant difference in the stages of change between pre-test and post-test (χ2 = 43.89, p < .001), and the change effect in the experimental group was better than that in the control group. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The proposed motivational interview intervention can help patients with type 2 diabetes admitted to medical wards improve their self-efficacy, self-care behavior, and glycated hemoglobin values. In the future, nursing education should improve the teaching of motivational interview skills to allow nurses to conduct effective interviews quickly during treatment, increase their patients' motivation to self-control blood sugar, and enable patients to learn blood sugar control skills before discharge to achieve effective blood sugar control.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/terapia , Controle Glicêmico , Autoeficácia , Glicemia , Hemoglobinas Glicadas
12.
Angew Chem Int Ed Engl ; 62(51): e202314398, 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-37920926

RESUMO

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.

13.
Angew Chem Int Ed Engl ; 62(48): e202312203, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37803457

RESUMO

(Hetero)arene reduction is one of the key avenues for synthesizing related cyclic alkenes and alkanes. While catalytic hydrogenation and Birch reduction are the two broadly utilized approaches for (hetero)arene reduction across academia and industry over the last century, both methods have encountered significant chemoselectivity challenges. We hereby introduce a highly chemoselective quinoline and isoquinoline reduction protocol operating through selective energy transfer (EnT) catalysis, which enables subsequent hydrogen atom transfer (HAT). The design of this protocol bypasses the conventional metric of reduction reaction, that is, the reductive potential, and instead relies on the triplet energies of the chemical moieties and the kinetic barriers of energy and hydrogen atom transfer events. Many reducing labile functional groups, which were incompatible with previous (hetero)arene reduction reactions, are retained in this reaction. We anticipate that this protocol will trigger the further advancement of chemoselective arene reduction and enable the current arene-rich drug space to escape from flatland.

14.
Medicine (Baltimore) ; 102(32): e34672, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37565874

RESUMO

BACKGROUND: Propranolol is the first choice for treating infantile hemangioma (IH). How propranolol works in IH remains unclear. Infantile hemangioma endothelial cells (HemECs) express Notch1, Jagged, Hey1, and other molecules in the Notch pathway, suggesting that Notch pathway-related molecules play an important role in affecting vascular endothelial cell proliferation. Whether propranolol can affect the Notch signaling pathway in IH treatment is unclear. METHODS: We performed this study to observe the effect of propranolol on the expression of Notch signaling pathway molecules in human umbilical vein endothelial cells (HUVECs) and to explore the therapeutic mechanism of propranolol on IH. HUVECs cultured in vitro were exposed to 60, 120, 240, 360, or 480 µM propranolol. The morphological changes of the HUVECs were observed under an inverted microscope. HUVECs proliferation was detected with Cell Counting Kit-8 (CCK-8). The effects of propranolol on HUVECs apoptosis were detected by flow cytometry. The role of Notch in propranolol inhibition of HUVEC proliferation was analyzed with real-time polymerase chain reaction (PCR) and western blotting. RESULTS: Propranolol reduced HUVECs numbers and altered their morphology. The inhibitory effect of propranolol on cell proliferation was dependent on the reaction time and drug concentration. Propranolol upregulated Jagged1, Notch1, and Hey1 expression and downregulated delta-like ligand4 (DLL4) expression. CONCLUSIONS: Propranolol may play a role in IH treatment by increasing Jagged1 expression in endothelial cells, activating the Notch pathway and inducing the upregulation of the downstream target gene HEY1.


Assuntos
Hemangioma , Propranolol , Humanos , Células Endoteliais da Veia Umbilical Humana , Propranolol/farmacologia , Propranolol/uso terapêutico , Transdução de Sinais/genética , Hemangioma/tratamento farmacológico , Hemangioma/genética , Biologia , Proliferação de Células
15.
Dimens Crit Care Nurs ; 42(5): 255-262, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37523724

RESUMO

OBJECTIVES: Studies have identified many nursing interventions that can prevent delirium and fall accidents in clinical patients, detect and treat delirium early to prevent functional decline in the patient, shorten hospitalization duration, and lower the death rate. This study aimed to explore delirium care by intensive care unit (ICU) nurses in a medical center of southern Taiwan. METHODS: This study conducted 3 semistructured focus group interviews, each for a single medical ICU, involving groups of 6 to 8 nurses each. The nurses were recruited through purposive sampling. This research was approved by an institutional review board in the medical center of southern Taiwan from March 31, 2020, to January 30, 2021. The co-principal investigator described the purpose and process of this study to the participants before they provided their written informed consents. The interviews were conducted in the meeting room and were audiotape recorded. The recordings were transcribed and subject to content analysis to identify the themes of delirium care. RESULTS: For nursing interventions of delirium, satisfying the patient's physical needs: comfort care, massages, and early rehabilitation; and psychological care: being presence, communication, and ensuring familial support were included. In terms of environmental interventions for delirium, providing reorientation, music, light, belongings with sentimental value, and audiovisual equipment were included. However, according to the recruited medical ICU nurses, these nonpharmacological interventions, although effective, do not have long-lasting effects. Finally, nurses reported themselves as having been attacked by patients with delirium. Thus, they all agreed that restraining patients with delirium may be necessary, but restraining is a double-edged sword for ICU delirium patients. CONCLUSIONS: Research team suggests for future studies to extend their evidence-based findings of physical, psychological, and environmental care for ICU delirium patients toward integrating the efforts of various health care professionals.


Assuntos
Delírio , Humanos , Grupos Focais , Taiwan , Delírio/diagnóstico , Unidades de Terapia Intensiva , Cuidados Críticos
16.
Mediators Inflamm ; 2023: 7123568, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37124060

RESUMO

Immunotherapy based on immune checkpoint inhibitors (ICIs) is considered to be a promising treatment for stomach adenocarcinoma (STAD), but only a minority of patients benefit from it. It is believed that the poor therapeutic efficacy is attributed to the complex tumor immune microenvironment (TIM) of STAD. Therefore, elucidating the specific regulatory mechanism of TIM in STAD is critical. Previous study suggests that GRP176 may be involved in regulating the pace of circadian behavior, and its role in tumors has not been reported. In this study, we first found that GPR176 was highly expressed in STAD and negatively correlated with patient prognosis. Next, we investigated the relationship between GPR176 and clinical characteristics, and the results showed that the stage is closely related to the level of GPR176. In addition, our further analysis found that GRP176 expression level was significantly correlated with chemotherapeutic drug sensitivity and ICI response. KEGG and GO analyses showed that GPR176 might be involved in stromal remodeling of STAD. Furthermore, we analyzed the association between GPR176 expression and immune implication, and the results revealed that GPR176 was negatively related to the infiltration of various immune cells. Interestingly, GPR176 induced the conversion of TIM while reducing the tumor immune burden (TMB). The expression of GRP176 is closely related to the level of various immunomodulators. Moreover, we performed univariate and multivariate regression analyses on the immunomodulators and finally obtained 4 genes (CRCR4, TNSF18, PDCD1, and TGFB1). Then, we constructed a GRP176-related immunomodulator prognostic model (GRIM) based on the above 4 genes, which was validated to have good predictive power. Finally, we developed a nomogram based on the risk score of GRIM and verified its accuracy. These results suggested that GPR176 is closely related to the prognosis and TIM of STAD. GPR176 may be a new potential target for immunotherapy in STAD.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Prognóstico , Biomarcadores , Adenocarcinoma/genética , Neoplasias Gástricas/genética , Adjuvantes Imunológicos , Microambiente Tumoral
17.
Angew Chem Int Ed Engl ; 62(23): e202303271, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37013706

RESUMO

Defluorinative manipulation of polyfluorinated molecules has shown great promise due to its granting of synthetic versatility to inert C-F bonds. The development of chemo-, stereo- and regioselective strategies to realize highly efficient formation of either the linear/branched or E/Z products from gem-difluorocyclopropanes (gem-F2 CPs) is a challenging task. Herein, we have realized palladium/NHC-catalyzed fluoroallylation/annulation of hydrazones with gem-F2 CPs that incorporate the hydrazone N2 moiety into the products. The thermodynamically unstable fluorinated E-allylation products with aryl ketone hydrazones were obtained for the first time, while the di-alkyl ketone hydrazones yielded the monofluorinated products with branched selectivity under similar reaction conditions. With aldehyde hydrazones, two kinds of pyrazoles were obtained via a defluorinative allylation/annulation cascade, in which different carbon atoms of gem-F2 CPs could be incorporated into the pyrazole rings regiospecifically. DFT calculations revealed that the divergent selectivity was kinetically controlled and the final C-C bond formation proceeded through a 7-membered TS.

18.
Acta Pharmacol Sin ; 44(6): 1217-1226, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36650291

RESUMO

Retinoic-acid-receptor-related orphan receptor γ (RORγ) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORγ deficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic islet ß cell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORγ inverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORγ transcriptional activity with a distinct cofactor recruitment profile from known RORγ ligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORγ ligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORγ to adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a RORγ-dependent manner. This study demonstrates a novel regulatory function of RORγ with linkage of the IL-17A pathway in pancreatic ß cells, and provides a valuable molecule for further investigating RORγ functions in treating T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Panax , Animais , Camundongos , Interleucina-17/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ligantes , Agonismo Inverso de Drogas , Panax/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas
19.
Heliyon ; 9(1): e12845, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36704277

RESUMO

With the continuous improvement of human's requirements for temperature control suitable for living, the energy consumption of electrical appliances such as air conditioners has become a major challenge in traditional architectural design. Generally, most of the solar energy passes through the glass to enter and exit the building, but the traditional glass can hardly control the light and heat energy, causing the indoor temperature to change dramatically with the environment. Therefore, it is more urgent to develop green and efficient smart windows. Perovskite is a temperature-adaptive material, which has the ability of phase transition and can adjust its band gap for thermochromic applications. In this work, we study the perovskite-based thermochromic smart window. As a new application of perovskite, a number of experiments have been carried out. However, there is still a lack of theoretical analysis on phase transition mechanisms and crystal structure prediction. Density functional theory (DFT) calculation is the most useful tool in optoelectronics, especially for perovskite crystal. Here, we extracted typical cases from published literature for analysis and comparison and summarized the crystal structure, electronic structure stability, interface engineering, and thermal characteristics employing DFT calculation We believe this work will pave the way for DFT application for the study of thermochromic perovskite.

20.
Int Health ; 15(4): 376-382, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35726866

RESUMO

BACKGROUND: The aim of the current study was to develop and validate a Perceived Relocation Stress Scale. METHODS: A cross-sectional research design was used. A total of 175 older adults residing in long-term care facilities in Southern Taiwan for at least 1 y were recruited. An exploratory factor analysis was performed to examine item convergent and discriminant validity. Concurrent validity was checked using the Depression Anxiety and Stress scale. The reliability was analyzed using Cronbach's alpha and intraclass correlation coefficients. RESULTS: The face and content validity of the scale were verified by adequately measuring the scale items. Factor analysis consisted of four components (challenge/chance, positive appraisal, threat, loss), with a total variance of 67.35%. The content validity was determined by an expert panel to systematically examine the relevance of all items. The results of item convergent and discriminant validity supported the constructs of the scale. The alpha coefficient for the overall scale was .958, indicating good internal consistency reliability. CONCLUSIONS: The Perceived Relocation Stress Scale is a reliable and valid measurement to assess the stress perceived by older individuals being transferred to a long-term care facility.


Assuntos
Instalações de Saúde , Assistência de Longa Duração , Humanos , Idoso , Taiwan , Reprodutibilidade dos Testes , Estudos Transversais , Inquéritos e Questionários
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