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1.
EMBO Rep ; 25(3): 1055-1074, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38351372

RESUMO

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-ß (TGF-ß), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-ß-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP-IFT88 axis as a potential therapeutic target for liver fibrosis.


Assuntos
Cílios , Cirrose Hepática , Animais , Camundongos , Cílios/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fator de Crescimento Transformador beta/metabolismo
2.
J Cell Physiol ; 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38308657

RESUMO

Primary cilia are distributed extensively within the corneal epithelium and endothelium. However, the presence of cilia in the corneal stroma and the dynamic changes and roles of endothelial and stromal cilia in corneal homeostasis remain largely unknown. Here, we present compelling evidence for the presence of primary cilia in the corneal stroma, both in vivo and in vitro. We also demonstrate dynamic changes of both endothelial and stromal cilia during corneal development. In addition, our data show that cryoinjury triggers dramatic cilium formation in the corneal endothelium and stroma. Furthermore, depletion of cilia in mutant mice lacking intraflagellar transport protein 88 compromises the corneal endothelial capacity to establish the effective tissue barrier, leading to an upregulation of α-smooth muscle actin within the corneal stroma in response to cryoinjury. These observations underscore the essential involvement of corneal endothelial and stromal cilia in maintaining corneal homeostasis and provide an innovative strategy for the treatment of corneal injuries and diseases.

3.
Anim Reprod Sci ; 261: 107406, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38141547

RESUMO

In ruminants, establishment and maintenance of pregnancy depends upon a well-coordinated interaction between the conceptus and the maternal endometrium. Epidermal growth factor (EGF) is important for embryo implantation and pregnancy establishment. However, the regulatory mechanisms of EGF expression remain unclear. FOXO1, a member of the Forkhead box O (FOXO) subfamily of transcription factors, is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. In this study, we examined the spatiotemporal expression profile of EGF in goat uterus during early pregnancy (Day 0 to Day 50 of pregnancy) and verified that EGF expression was regulated by FOXO1 and interferon tau (IFNT). Our results showed that EGF was highly expressed in the luminal epithelium (LE) and the glandular epithelium (GE) during conceptus adhesion (Day 16 to Day 25 of pregnancy). After implantation, EGF protein signals were continuously detected in the endometrial epithelia and appeared in the conceptus trophectoderm. Furthermore, EGF expression could be up-regulated by IFNT in goat uterus and primary endometrial epithelium cells (EECs). The luciferase assay results showed that FOXO1 could promote EGF transcription by binding to its promoter. And FOXO1 positively regulates EGF expression in goat EECs. These findings contribute to better understanding the role and regulation mechanisms of EGF during ruminant early pregnancy.


Assuntos
Endométrio , Fator de Crescimento Epidérmico , Interferon Tipo I , Proteínas da Gravidez , Gravidez , Humanos , Feminino , Animais , Camundongos , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Endométrio/metabolismo , Implantação do Embrião/fisiologia , Útero/metabolismo , Ruminantes , Cabras , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo
4.
J Mol Cell Biol ; 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38059869

RESUMO

Carbohydrate metabolism disorders (CMDs), such as diabetes, galactosemia, and mannosidosis, cause ciliopathy-like multiorgan defects. However, the mechanistic link of cilia to CMD complications is still poorly understood. Herein, we describe a significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols. Moreover, environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups. Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane, which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly. In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella. These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.

5.
Artigo em Inglês | MEDLINE | ID: mdl-38148421

RESUMO

INTRODUCTION: Before tracheal intubation, it is essential to provide sufficient oxygen reserve for emergency patients with full stomachs. Recent studies have demonstrated that high-flow nasal oxygen (HFNO) effectively pre-oxygenates and prolongs apneic oxygenation during tracheal intubation. Despite its effectiveness, the use of HFNO remains controversial due to concerns regarding carbon dioxide clearance. The air leakage and unknown upper airway obstruction during HFNO therapy cause reduced oxygen flow above the vocal cords, possibly weaken the carbon dioxide clearance. METHODS: Patients requiring emergency surgery who had fasted < 8 h and not drunk < 2 h were randomly assigned to the high-flow group, who received 100% oxygen at 30-60 L/min through nasopharyngeal airway (NPA), or the mask group, who received 100% oxygen at 8 L/min. PaO2 and PaCO2 were measured immediately before pre-oxygenation (T0), anesthesia induction (T1), tracheal intubation (T2), and mechanical ventilation (T3). The gastric antrum's cross-sectional area (CSA) was measured using ultrasound technology at T0, T1, and T3. Details of complications, including hypoxemia, reflux, nasopharyngeal bleeding, postoperative pulmonary infection, postoperative nausea and vomiting (PONV), and postoperative nasopharyngeal pain, were recorded. The primary outcomes were PaCO2 measured at T1, T2, and T3. The secondary outcomes included PaO2 at T1, T2, and T3, CSA at T1 and T3, and complications happened during this trial. RESULTS: Pre-oxygenation was administered by high-flow oxygen through NPA (n = 58) or facemask (n = 57) to 115 patients. The mean (SD) PaCO2 was 32.3 (6.7) mmHg in the high-flow group and 34.6 (5.2) mmHg in the mask group (P = 0.045) at T1, 45.0 (5.5) mmHg and 49.4 (4.6) mmHg (P < 0.001) at T2, and 47.9 (5.1) mmHg and 52.9 (4.6) mmHg (P < 0.001) at T3, respectively. The median ([IQR] [range]) PaO2 in the high-flow and mask groups was 404.5 (329.1-458.1 [159.8-552.9]) mmHg and 358.9 (274.0-413.3 [129.0-539.1]) mmHg (P = 0.007) at T1, 343.0 (251.6-428.7 [73.9-522.1]) mmHg and 258.3 (162.5-347.5 [56.0-481.0]) mmHg (P < 0.001) at T2, and 333.5 (229.9-411.4 [60.5-492.4]) mmHg and 149.8 (87.0-246.6 [51.2-447.5]) mmHg (P < 0.001) at T3, respectively. The CSA in the high-flow and mask groups was 371.9 (287.4-557.9 [129.0-991.2]) mm2 and 386.8 (292.0-537.3 [88.3-1651.7]) mm2 at T1 (P = 0.920) and 452.6 (343.7-618.4 [161.6-988.1]) mm2 and 385.6 (306.3-562.0 [105.5-922.9]) mm2 at T3 (P = 0.173), respectively. The number (proportion) of complications in the high-flow and mask groups is shown below: hypoxemia: 1 (1.7%) vs. 9 (15.8%, P = 0.019); reflux: 0 (0%) vs. 0 (0%); nasopharyngeal bleeding: 1 (1.7%) vs. 0 (0%, P = 1.000); pulmonary infection: 4 (6.9%) vs. 3 (5.3%, P = 1.000); PONV: 4 (6.9%) vs. 4 (7.0%, P = 1.000), and nasopharyngeal pain: 0 (0%) vs. 0 (0%). CONCLUSIONS: Compared to facemasks, pre-oxygenation with high-flow oxygen through NPA offers improved carbon dioxide clearance and enhanced oxygenation prior to tracheal intubation in patients undergoing emergency surgery, while the risk of gastric inflation had not been ruled out. TRIAL REGISTRATION: This trial was registered prospectively at the Chinese Clinical Research Registry on 26/4/2022 (Registration number: ChiCTR2200059192).

6.
Adv Sci (Weinh) ; 10(36): e2303545, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37963851

RESUMO

O-GlcNAcylation functions as a cellular nutrient and stress sensor and participates in almost all cellular processes. However, it remains unclear whether O-GlcNAcylation plays a role in the establishment and maintenance of cell polarity, because mice lacking O-GlcNAc transferase (OGT) are embryonically lethal. Here, a mild Ogt knockout mouse model is constructed and the important role of O-GlcNAcylation in establishing and maintaining cell polarity is demonstrated. Ogt knockout leads to severe pulmonary fibrosis and dramatically promotes epithelial-to-mesenchymal transition. Mechanistic studies reveal that OGT interacts with pericentriolar material 1 (PCM1) and centrosomal protein 131 (CEP131), components of centriolar satellites required for anchoring microtubules to the centrosome. These data further show that O-GlcNAcylation of PCM1 and CEP131 promotes their centrosomal localization through phase separation. Decrease in O-GlcNAcylation prevents PCM1 and CEP131 from localizing to the centrosome, instead dispersing these proteins throughout the cell and impairing the microtubule-centrosome interaction to disrupt centrosome positioning and cell polarity. These findings identify a previously unrecognized role for protein O-GlcNAcylation in establishing and maintaining cell polarity with important implications for the pathogenesis of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/metabolismo , Polaridade Celular , Centrossomo/metabolismo , Fenótipo
7.
Pathol Oncol Res ; 29: 1611330, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37746555

RESUMO

Systemic capillary leak syndrome (SCLS) is a rare and complex adverse effect of immune checkpoint inhibitors (ICIs). The diagnosis of drug-induced SCLS is based on diffuse infusions of exudative fluid into the interstitial areas and the exclusion of other causes. The best management of ICIs-induced SCLS is not settled, though proper supportive care and corticosteroids were commonly applied as the first-line treatment. In our patient with advanced gastroesophageal junction squamous cell carcinoma, although ICIs-induced SCLS was successfully controlled with corticosteroids, the patient soon experienced cancer progress and died of pulmonary infections. Based on our experience and the reported cases by other hospitals, different stages of SCLS might respond differently to the same treatment. Therefore, a grading of ICIs-induced SCLS might help to stratify the patient for different treatment strategies. Besides, corticosteroids-sensitive patients, though waived from deadly SCLS, might be at higher risk of cancer progress and subsequent infections due to the application of corticosteroids. Considering that the inflammatory factors should be closely involved in the development of ICIs-induced SCLS, targeted therapy against the driver inflammatory cytokine might offer treatment regimens that are more effective and safer.


Assuntos
Síndrome de Vazamento Capilar , Carcinoma de Células Escamosas , Humanos , Síndrome de Vazamento Capilar/induzido quimicamente , Síndrome de Vazamento Capilar/diagnóstico , Síndrome de Vazamento Capilar/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células Escamosas/complicações , Corticosteroides/uso terapêutico
8.
J Cell Physiol ; 238(11): 2600-2611, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37683035

RESUMO

The primary cilium is increasingly recognized as a crucial player in the physiology of biliary epithelial cells (BECs). However, the precise role of primary cilia in the development of age-related biliary fibrosis remains unclear. Herein, using cilium-deficient mice, we demonstrate that disruption of ciliary homeostasis in BECs in aged mice leads to significant bile duct proliferation, augmented biliary fibrosis, and heightened indicators of liver injury. Our RNA-sequencing data revealed a dysregulation in genes associated with various biological processes such as bile secretion, fatty acid metabolism, and inflammation. Loss of primary cilia also significantly enhanced signaling pathways driving the development of biliary fibrosis. Our findings collectively suggest that loss of primary cilia in the BECs of aged mice initiates a cascade of signaling events that contribute to biliary fibrosis, highlighting the primary cilium as a potential therapeutic target in the treatment of fibrosing cholangiopathies.


Assuntos
Cílios , Hepatopatias , Animais , Camundongos , Cílios/metabolismo , Hepatopatias/metabolismo , Células Epiteliais/metabolismo , Fibrose
9.
Clin Interv Aging ; 18: 1565-1576, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37727450

RESUMO

Purpose: Dexmedetomidine exerts a neuroprotective effect, however, the mechanism underlying this effect remains unclear. This study aimed to explore whether dexmedetomidine can reduce the increase in neurofilament light chain (NfL) protein concentration to play a neuroprotective role during thoracoscopic surgery. Patients and Methods: Patients aged ≥60 years undergoing general anesthesia for thoracoscopic surgery were randomly assigned to receive dexmedetomidine (group D) or not receive dexmedetomidine (group C). Patients in group D received a loading dose of dexmedetomidine 0.5 µg/kg before anesthesia induction and a continuous infusion at 0.5 µg·kg-1·h-1 until the end of the surgery. Dexmedetomidine was not administered in group C. The primary outcome was the NfL concentration on postoperative day 1. The concentrations of procalcitonin (PCT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were detected preoperatively and on postoperative day 1. In addition, the numerical rating scale (NRS) and quality of recovery-40 (QoR-40) scores were evaluated. Results: A total of 38 patients in group D and 37 in group C were included in the analysis. No differences were observed between the groups in terms of the plasma concentration of NfL preoperatively and on postoperative day 1 (11.17 [8.86, 13.93] vs 13.15 [10.76, 15.56] pg/mL, P > 0.05; 16.70 [12.23, 21.15] vs 19.48 [15.25, 22.85] pg/mL, P > 0.05, respectively). However, the postoperative plasma NfL concentration was significantly higher than the preoperative value in both groups (both P < 0.001). The groups exhibited no differences in PCT, SAA, hs-CRP, NRS, and QoR-40 (all P > 0.05). Conclusion: Intraoperative administration of dexmedetomidine at a conventional dose does not appear to significantly reduce the increase in postoperative plasma NfL concentration in elderly patients undergoing thoracoscopic surgery. This finding suggests that the neuroprotective effect of dexmedetomidine at a conventional dose was not obvious during general anesthesia.


Assuntos
Proteína C-Reativa , Fármacos Neuroprotetores , Idoso , Humanos , Filamentos Intermediários , Estudos Prospectivos , Anestesia Geral
10.
EMBO Rep ; 24(10): e56009, 2023 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-37642636

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) are cells mainly present in the bone marrow and capable of forming mature blood cells. However, the epigenetic mechanisms governing the homeostasis of HSPCs remain elusive. Here, we demonstrate an important role for histone deacetylase 6 (HDAC6) in regulating this process. Our data show that the percentage of HSPCs in Hdac6 knockout mice is lower than in wild-type mice due to decreased HSPC proliferation. HDAC6 interacts with isocitrate dehydrogenase 1 (IDH1) and deacetylates IDH1 at lysine 233. The deacetylation of IDH1 inhibits its catalytic activity and thereby decreases the 5-hydroxymethylcytosine level of ten-eleven translocation 2 (TET2) target genes, changing gene expression patterns to promote the proliferation of HSPCs. These findings uncover a role for HDAC6 and IDH1 in regulating the homeostasis of HSPCs and may have implications for the treatment of hematological diseases.


Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Animais , Camundongos , Desacetilase 6 de Histona/genética , Desacetilase 6 de Histona/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células da Medula Óssea/metabolismo , Homeostase
11.
J Dairy Sci ; 106(11): 8060-8071, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37268579

RESUMO

In ruminants, IFN-tau (IFNT) regulates the production of prostaglandins (PG) in the endometrium, which is crucial for conceptus adhesion. However, the related molecular regulatory mechanisms remain unclear. Forkhead box O1 (FOXO1), a member of the FOXO subfamily of transcription factors, is known to be important for mouse implantation and decidualization. In this study, we determined the spatiotemporal expression profile of FOXO1 in goat endometrium during early pregnancy. FOXO1 was highly expressed in the glandular epithelium since the onset of conceptus adhesion (d 16 of pregnancy). Then, we validated that FOXO1 could bind to the promoter of prostaglandin-endoperoxide synthase 2 (PTGS2) and increase its transcription. And the expression profile of PTGS2 was similar to that of FOXO1 in the peri-implantation uterus. Moreover, IFNT could upregulate the levels of FOXO1 and PTGS2 in goat uterus and primary endometrial epithelium cells (EEC). In EEC, the intracellular content of PGF2α was positively correlated with the levels of IFNT and FOXO1. Altogether, we found an IFNT/FOXO1/PTGS2 axis that controls the synthesis of PGF2α but not prostaglandin E2 in goat uterine glands. These findings contribute to better understanding the function of FOXO1 in the reproductive physiology of goats and provide more insights into the implantation of small ruminants.

12.
Cell Tissue Res ; 392(3): 733-743, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36988705

RESUMO

The non-receptor tyrosine kinase Src plays a key role in cell division, migration, adhesion, and survival. Src is overactivated in several cancers, where it transmits signals that promote cell survival, mitosis, and other important cancer hallmarks. Src is therefore a promising target in cancer therapy, but the underlying mechanisms are still uncertain. Here we show that Src is highly conserved across different species. Src expression increases during mitosis and is localized to the chromosomal passenger complex. Knockdown or inhibition of Src induces multipolar spindle formation, resulting in abnormal expression of the Aurora B and INCENP components of the chromosomal passenger complex. Molecular mechanism studies have found that Src interacts with and phosphorylates INCENP. This then leads to incorrect chromosome arrangement and segregation, resulting in cell division failure. Herein, Src and chromosomal passenger complex co-localize and Src inhibition impedes mitotic progression by inducing multipolar spindle formation. These findings provide novel insights into the molecular basis for using Src inhibitors to treat cancer.


Assuntos
Antineoplásicos , Genes src , Mitose , Proteínas Proto-Oncogênicas pp60(c-src) , Humanos , Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/metabolismo , Citoesqueleto/metabolismo , Genes src/efeitos dos fármacos , Mitose/efeitos dos fármacos , Fuso Acromático/genética , Fuso Acromático/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/antagonistas & inibidores , Antineoplásicos/farmacologia
13.
Biol Reprod ; 108(6): 902-911, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-36917263

RESUMO

N6-methyladenosine (m6A), an epigenetic modification on RNAs, plays an important role in many physiological and pathological processes. However, the involvement of m6A in goat uterus during early pregnancy remains largely unknown. In this study, we found that the total m6A level was increasing in goat uterus as early pregnancy progressed. Methyltransferase-like 3 (METTL3) is a core catalytic subunit of the m6A methyltransferase. We thus determined the expression and regulation of METTL3 in goat uterus. METTL3 was highly expressed in the luminal and glandular epithelia from day 16 (D16) to D25 of pregnancy, and it could be up-regulated by estrogen and progesterone in goat uterus and primary endometrial epithelial cells (EECs). In EECs, knockdown or overexpression of METTL3 resulted in a significant decrease or increase of cell proliferation, respectively. METTL3 knockdown reduced the m6A level of not only total RNA but also connective tissue growth factor (CTGF) mRNA. Luciferase assay suggested that METTL3 might target the potential m6A sites in the 3'untranslated region (3'UTR) of CTGF mRNA. Moreover, METTL3 positively regulated CTGF expression, and CTGF knockdown significantly counteracted the promoting effect of METTL3 overexpression on EEC proliferation. Collectively, METTL3 is dynamically expressed in goat uterus and can affect EEC proliferation by regulating CTGF in an m6A-dependent manner. Our results will lay a foundation for further studying the crucial mechanism of METTL3-mediated m6A modification in goat uterus during early pregnancy.


Assuntos
Fator de Crescimento do Tecido Conjuntivo , Cabras , Animais , Feminino , Fator de Crescimento do Tecido Conjuntivo/genética , Cabras/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Células Epiteliais/metabolismo , RNA Mensageiro/metabolismo , Proliferação de Células/genética
14.
Chem Commun (Camb) ; 59(17): 2489-2492, 2023 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-36752553

RESUMO

By inserting a tricoordinate B atom into an indolo[3,2,1-jk]carbazole precursor, an efficient fused multiple resonance-induced thermally activated delayed fluorescence emitter was prepared, which exhibits a narrowband emission and a considerable reverse intersystem crossing rate. The corresponding organic light-emitting diode displays an external quantum efficiency of 27.2% with a suppressed efficiency roll-off.

15.
J Genet Genomics ; 50(7): 486-496, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36796536

RESUMO

O-GlcNAcylation is a post-translational modification that serves as a cellular nutrient sensor and participates in multiple physiological and pathological processes. However, it remains uncertain whether O-GlcNAcylation is involved in the regulation of phagocytosis. Here, we demonstrate a rapid increase in protein O-GlcNAcylation in response to phagocytotic stimuli. Knockout of the O-GlcNAc transferase or pharmacological inhibition of O-GlcNAcylation dramatically blocks phagocytosis, resulting in the disruption of retinal structure and function. Mechanistic studies reveal that the O-GlcNAc transferase interacts with Ezrin, a membrane-cytoskeleton linker protein, to catalyze its O-GlcNAcylation. Our data further show that Ezrin O-GlcNAcylation promotes its localization to the cell cortex, thereby stimulating the membrane-cytoskeleton interaction needed for efficient phagocytosis. These findings identify a previously unrecognized role for protein O-GlcNAcylation in phagocytosis with important implications in both health and diseases.


Assuntos
Fagocitose , Processamento de Proteína Pós-Traducional , Acetilglucosamina/metabolismo , Citoplasma/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Animais , Camundongos
16.
Clin Cancer Res ; 29(4): 805-814, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36441798

RESUMO

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.


Assuntos
Neoplasias da Mama , Paclitaxel , Humanos , Feminino , Paclitaxel/uso terapêutico , Trastuzumab/uso terapêutico , Terapia Neoadjuvante , Biomarcadores Tumorais/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , RNA
17.
PLoS One ; 17(10): e0275793, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36227845

RESUMO

BACKGROUND: The aim of this study is to evaluate analgesic efficacy of pericapsular nerve group (PENG) block in patients with intertrochanteric femur fracture (IFF). METHODS: This double-blinded randomized controlled trial in patients with IFF scheduled for proximal femoral nail antirotation (PFNA) between December 2020 and November 2021. The primary outcome was VAS scores during exercising at 6 h after surgery; secondary outcomes were pain during exercising and rest, intraoperative dose of remifentanil, cumulative dose of postoperative fentanyl, postoperative analgesia satisfaction scores, and ratio of quadriceps weakness. RESULTS: A total of 50 patients were randomly divided into PENG block group (n = 25) or fascia iliaca compartment block (FICB) group (n = 25). Exercising VAS scores at 6 h after surgery were significantly lower in PENG block group than that in FICB group (2 (2, 4) vs. 6 (4, 7), P < 0.001). The intraoperative dose of remifentanil and cumulative dose of postoperative fentanyl by patient-controlled intravenous analgesia within 24 h after surgery in PENG block group were significantly lower than in FICB group (both P < 0.001). Postoperative analgesia satisfaction scores in PENG block group were significantly higher than those in FICB group (P = 0.016). The ratio of quadriceps weakness at 6 h after surgery was significantly higher in FICB group than PENG block group (48% vs. 0%, P < 0.001). CONCLUSIONS: Compared to FICB, ultrasound-guided PENG block may provide better postoperative pain relief in patients with IFF, with less pronounced quadriceps weakness.


Assuntos
Nervo Femoral , Fraturas do Quadril , Analgésicos , Fêmur , Fentanila , Fraturas do Quadril/cirurgia , Humanos , Dor Pós-Operatória/tratamento farmacológico , Remifentanil
18.
Angew Chem Int Ed Engl ; 61(41): e202209984, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-35981975

RESUMO

Herein, we report two multiple-resonance thermally activated delayed fluorescence emitters (VTCzBN and TCz-VTCzBN) based on indolo[3,2,1-jk]carbazole unit and boron-nitrogen skeletons, whose emissions peaking at 496 and 521 nm with full width at half maximum of 34 and 29 nm, respectively. Meanwhile, fast rate constants of reverse intersystem crossing of above 106  s-1 are obtained due to small singlet-triplet energy gaps and large spin-orbital coupling values. Notably, planar molecular structures along the transition dipole moment direction endow them with high horizontal emitting dipole ratios of up to 94 %. Consequently, the corresponding organic light-emitting diodes (OLEDs) show the maximum external quantum efficiencies of 31.7 % and 32.2 %, respectively. Particularly, OLED with TCz-VTCzBN display ultra-pure green emission with Commission Internationale de l'Eclairage coordinates of (0.22, 0.71), consistent with the green display standard of the National Television System Committee.

19.
Contrast Media Mol Imaging ; 2022: 3670007, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35845743

RESUMO

To investigate the changes in bone mineral density, bone metabolism, and efficacy of nutritional intervention combined with calcium carbonate D3 tablets in patients with osteoporosis, a RevMan 5.2 software meta-analysis was conducted in this study. According to the therapeutic direction of nutritional intervention combined with calcium carbonate D3 tablets for osteoporosis patients, relevant literature were searched in Wanfang Medical, CNKI, VIP, and PubMed literature databases at home and abroad. Keywords included bone mineral density, bone metabolism, blood calcium (Ca), blood phosphorus (P), osteocalcin (OC), bone mineral density (BMD), serum alkaline phosphatase (ALP), efficacy, osteoporosis, and nutritional intervention. Literature that met the criteria were deleted, and meta-analysis was performed using RevMan 5.2 software. The results indicate that a total of 10 Chinese literature were included. Compared with the monotherapy group, the clinical efficacy, osteocalcin, BMD, alkaline phosphatase, calcium, and phosphorus were significantly higher in the combination group (P < 0.05). Based on calcium carbonate D3, treatment combined with nutritional intervention can enhance the clinical efficacy, bone metabolism, and bone mineral density of patients with osteoporosis, and nutritional intervention combined with calcium carbonate D3 tablets is a feasible program to promote the recovery of patients with osteoporosis.


Assuntos
Densidade Óssea , Osteoporose , Fosfatase Alcalina/farmacologia , Fosfatase Alcalina/uso terapêutico , Cálcio/farmacologia , Cálcio/uso terapêutico , Carbonato de Cálcio/farmacologia , Carbonato de Cálcio/uso terapêutico , Humanos , Osteocalcina/farmacologia , Osteocalcina/uso terapêutico , Osteoporose/tratamento farmacológico , Fósforo/farmacologia , Fósforo/uso terapêutico , Comprimidos/farmacologia , Comprimidos/uso terapêutico
20.
Adv Mater ; 34(36): e2204253, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35839149

RESUMO

The realization of luminescent materials with narrowband and circularly polarized luminescence (CPL) is of great significance for the development of future optical and photonic devices. Herein, through a steric-hindrance-assisted dual-core strategy, two pairs of chiral dual-core multiple resonance thermally activated delayed fluorescence (MR-TADF) materials (R/S-DOBN and R/S-DOBNT) are directly constructed by the bonding of two organoboron MR-TADF monocores (SOBN and SOBNT) with carbazole/3,6-di-tert-butyl-9H-carbazole and phenol derivative as donors, realizing obvious CPL and narrowband emissions. Furthermore, the dual-core effect in the prepared R/S-DOBN and R/S-DOBNT increases the transition oscillator strength two times more than that of a monocore structure, while maintaining the ultrapure blue emissions peaking at 453 and 459 nm with a narrower full-width at half-maximum of 21 nm through reorganization energy reduction. The circularly polarized organic light-emitting diodes based on the enantiomers exhibit ultrapure blue emission with Commission Internationale de L'Eclairage (CIE) coordinates of (0.14, 0.10) and (0.13, 0.12), high maximum external quantum efficiencies of 23.9% and 25.6%, and obvious circularly polarized electroluminescence with dissymmetry factors (|gEL |) ≈ 10-3 .

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