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1.
Mol Cell ; 83(16): 3010-3026.e8, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37595559

RESUMO

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and U1-70K-containing RNA-splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.


Assuntos
Arginina , Lipogênese , Proteína de Ligação a Elemento Regulador de Esterol 1 , Lipogênese/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fatores de Processamento de RNA , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Humanos , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo
2.
Nature ; 629(8014): 1174-1181, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38720073

RESUMO

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.


Assuntos
Fosfotirosina , Proteínas Tirosina Quinases , Especificidade por Substrato , Tirosina , Animais , Humanos , Motivos de Aminoácidos , Evolução Molecular , Espectrometria de Massas , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Fosforilação , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Proteoma/química , Proteoma/metabolismo , Proteômica , Transdução de Sinais , Domínios de Homologia de src , Tirosina/metabolismo , Tirosina/química
3.
Nature ; 613(7945): 759-766, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36631611

RESUMO

Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.


Assuntos
Fosfoproteínas , Proteínas Serina-Treonina Quinases , Proteoma , Serina , Treonina , Humanos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , Especificidade por Substrato , Treonina/metabolismo , Proteoma/química , Proteoma/metabolismo , Conjuntos de Dados como Assunto , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Linhagem Celular , Fosfosserina/metabolismo , Fosfotreonina/metabolismo
4.
Cell Mol Life Sci ; 81(1): 29, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38212474

RESUMO

Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning causes distension of the alveolar structures due to the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2-4 h of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GCaMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression but prior to significant activation of LDCD or its previously implicated mediators such as LIF, IL6, and TGFß3, all of which appear to be upregulated by increased intracellular calcium. We further demonstrate that increased intracellular calcium activates STAT3 by inducing degradation of its negative regulator, SOCS3. We also observed that milk stasis, loss of PMCA2 expression and increased intracellular calcium levels activate TFEB, an important regulator of lysosome biogenesis through a process involving inhibition of CDK4/6 and cell cycle progression. In summary, these data suggest that intracellular calcium serves as an important proximal biochemical signal linking milk stasis to STAT3 activation, increased lysosomal biogenesis, and lysosome-mediated cell death.


Assuntos
Cálcio , Leite , Feminino , Animais , Leite/metabolismo , Cálcio/metabolismo , Morte Celular , Lactação , Lisossomos/metabolismo , Glândulas Mamárias Animais/metabolismo , Fator de Transcrição STAT3/metabolismo
5.
Planta Med ; 90(1): 4-12, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37903549

RESUMO

Agastache rugosa Kuntze (Lamiaceae; Labiatae), a medicinal and functional herb used to treat gastrointestinal diseases, grows well both on islands and inland areas in South Korea. Thus, we aimed to reveal the morphological and micromorphological differences between A. rugosa grown on island and inland areas and their pharmacological effects on gastritis in an animal model by combining morphological and mass spectrophotometric analyses. Morphological analysis showed that island A. rugosa had slightly smaller plants and leaves than inland plants; however, the density of all types of trichomes on the leaves, petioles, and stems of island A. rugosa was significantly higher than that of inland plants. The essential oil component analysis revealed that pulegone levels were substantially higher in island A. rugosa than in inland A. rugosa. Despite the differences between island and inland A. rugosa, treatment with both island and inland A. rugosa reduced gastric damages by more than 40% compared to the gastritis induction group. In addition, expression of inflammatory protein was reduced by about 30% by treatment of island and inland A. rugosa. The present study demonstrates quantitative differences in morphology and volatile components between island and inland plants; significant differences were not observed between the gastritis-inhibitory effects of island and inland A. rugosa, and the efficacy of island A. rugosa was found to be similar to that of A. rugosa grown in inland areas.


Assuntos
Agastache , Gastrite , Óleos Voláteis , Animais , Folhas de Planta , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Gastrite/induzido quimicamente , Gastrite/tratamento farmacológico
6.
Neurosurg Focus ; 54(1): E4, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36587410

RESUMO

OBJECTIVE: The goal of this study was to assess the outcomes of minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) in patients ≥ 70 years old and compare them to younger age groups. METHODS: This was a retrospective study of data that were collected prospectively. Patients who underwent primary single-level MI-TLIF were included and divided into 3 groups: age < 60, 60-69, and ≥ 70 years. The outcome measures were as follows: 1) patient-reported outcome measures (PROMs) (i.e., visual analog scale [VAS] for back and leg pain, Oswestry Disability Index [ODI], 12-Item Short-Form Health Survey Physical Component Summary [SF-12 PCS]); 2) minimum clinically important difference (MCID) achievement; 3) return to activities; 4) opioid discontinuation; 5) fusion rates; and 6) complications/reoperations. RESULTS: A total of 147 patients (age < 60 years, 62; 60-69 years, 47; ≥ 70 years, 38) were included. All the groups showed significant improvements in all PROMs at the early (< 6 months) and late (≥ 6 months) time points and there was no significant difference between the groups. Although MCID achievement rates for VAS leg and ODI were similar, they were lower in the ≥ 70-year-old patient group for VAS back and SF-12 PCS. Although the time to MCID achievement for ODI and SF-12 PCS was similar, it was greater in the ≥ 70-year-old patient group for VAS back and leg. There was no significant difference between the groups in terms of return to activities, opioid discontinuation, fusion rates, and complication/reoperation rates. CONCLUSIONS: Although patients > 70 years of age may be less likely and/or take longer to achieve MCID compared to their younger counterparts, they show an overall significant improvement in PROMs, a similar likelihood of returning to activities and discontinuing opioids, and comparable fusion and complication/reoperation rates following MI-TLIF.


Assuntos
Vértebras Lombares , Fusão Vertebral , Humanos , Idoso , Vértebras Lombares/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Analgésicos Opioides , Procedimentos Cirúrgicos Minimamente Invasivos
7.
Surg Technol Int ; 432023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37851301

RESUMO

BACKGROUND: The use of shoulder arthroplasty has increased among all age groups, albeit most prominently in older patients. While previous studies have investigated predictors of short-term readmission and reoperation in the general population, there is a paucity of literature available on these in patients under 45 years of age. This study aimed to identify the predictors of 30-day readmission and reoperation following shoulder arthroplasty in patients under 45 years of age. METHODS: A retrospective query in the American College of Surgeons National Surgical Quality Improvement Program database from 2011 to 2019 was used to identify patients who underwent primary reverse and anatomic total shoulder arthroplasty and hemiarthroplasty. Multivariate logistic regression was used to identify predictors of 30-day readmission and reoperation. RESULTS: A total of 530 patients were included. Multivariate regression revealed that Black race and Hispanic ethnicity were independent predictors of readmission. Functional dependence, hypertension requiring medication, and prolonged length of stay predicted reoperation. Finally, low hematocrit and prolonged length of stay predicted morbidity. DISCUSSION: Identifying and accounting for these risk factors for poor outcomes may help improve perioperative risk stratification. As a result, these findings have the potential to reduce healthcare costs associated with readmission and reoperation following shoulder arthroplasty in young patients. Our results also highlight the underlying disparities in healthcare outcomes among racial and ethnic groups that must be considered.

8.
Molecules ; 28(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36677905

RESUMO

Periodontitis is caused by pathogens in the oral cavity. It is a chronic infectious disease that causes symptoms including gingival bleeding and tooth loss resulting from the destruction of periodontal tissues coupled with inflammation. Dendropanax morbiferus H.Lév (DM) is a natural product that exhibits various biological activities with few side effects. In this study, the potential of DM leaf hot-water extracts (DMWE) as a treatment for periodontitis was determined and its anti-oxidant and anti-inflammatory effects were evaluated. Compounds in DMWE were identified by high-performance liquid chromatography (HPLC) and nitric oxide (NO) and prostaglandin E2 (PGE2) production was measured in RAW 264.7 cells. We measured the gingival index and gingival sulcus depth, and micro-CT was performed in vivo using a ligature-induced periodontitis rat model, which is similar to human periodontitis. The DMWE-treated group exhibited a decrease in cytokine concentration and relieved the gingival index and gingival sulcus depth compared with the periodontitis-induced control group. In addition, micro-CT and histological analysis revealed that DMWE exhibited anti-inflammatory effects and improved alveolar bone loss in periodontitis-induced rats. These findings suggest that DMWE has excellent anti-oxidant and anti-inflammatory effects that protect and prevent periodontal tissue damage and tooth loss caused by the inflammatory response.


Assuntos
Perda do Osso Alveolar , Periodontite , Perda de Dente , Ratos , Humanos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Perda de Dente/complicações , Perda de Dente/tratamento farmacológico , Modelos Animais de Doenças , Periodontite/patologia , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
9.
Nano Lett ; 18(9): 5506-5513, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30080971

RESUMO

Graphene-oxide (GO) membranes with notable ionic-sieving properties have attracted significant attention for many applications. However, the swelling and unstable nanostructure of GO laminates in water results in enlarged interlayer spacing and a low permeation cut-off, limiting their applicability for water purification and desalination. Herein, we propose novel nitrogen-doped graphene (NG) membranes for use in tunable ion sieving that are made via facile fabrication by a time-dependent N-doping technique. Doping reaction time associated variation in atomic content and bonding configurations strongly contributed to the nanostructure of NG laminates by yielding narrower interlayer spacing and a more-polarized surface than GO. These nanostructural features subsequently allowed ion transport through the combined mechanisms of size exclusion and electrostatic interaction. The stacked NG membranes provided size-dependent permeability for hydrated ions and improved ion selectivity by 1-3 orders of magnitude in comparison to that of a GO membrane. For ions small enough to move through the interlayer spacing, the ion permeation is determined by electrostatic properties of NG membranes with the type of N configuration, especially polarized pyridinic N. Due to these properties, the NG membrane functioned as an unconventionally selective graphene-based membrane with better ion sieving for water purification.

10.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163646

RESUMO

The genus Cuscuta (Convolvulaceae) comprises well-known parasitic plants. Cuscuta species are scientifically valuable, as their life style causes extensive crop damage. Furthermore, dried seeds of C. chinensis are used as a Korean traditional herbal medicine. Despite the importance of Cuscuta species, it is difficult to distinguish these plants by the naked eye. Moreover, plastid sequence information available for Cuscuta species is limited. In this study, we distinguished between C. chinensis and C. japonica using morphological characterisation of reproductive organs and molecular characterisation of chloroplast genomes. The differences in morphological characteristics of reproductive organs such as style, stigma, infrastaminal scale, seed shape and testa ornamentation were useful for distinguishing between C. japonica and C. chinensis. Analysis of chloroplast genomes revealed drastic differences in chloroplast genome length and gene order between the two species. Although both species showed numerous gene losses and genomic rearrangements, chloroplast genomes showed highly similar structure within subgenera. Phylogenetic analysis of Cuscuta chloroplast genomes revealed paraphyletic groups within subgenera Monogynella and Grammica, which is consistent with the APG IV system of classification. Our results provide useful information for the taxonomic, phylogenetic and evolutionary analysis of Cuscuta and accurate identification of herbal medicine.


Assuntos
Cuscuta/fisiologia , Genoma de Cloroplastos , Genoma de Planta , Genômica , Fenótipo , Reprodução , Cuscuta/citologia , Cuscuta/ultraestrutura , Ordem dos Genes , Estudos de Associação Genética , Genômica/métodos , Filogenia
11.
Molecules ; 24(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875988

RESUMO

The genus Angelica (Apiaceae) comprises valuable herbal medicines. In this study, we determined the complete chloroplast (CP) genome sequence of A. polymorpha and compared it with that of Ligusticum officinale (GenBank accession no. NC039760). The CP genomes of A. polymorpha and L. officinale were 148,430 and 147,127 bp in length, respectively, with 37.6% GC content. Both CP genomes harbored 113 unique functional genes, including 79 protein-coding, four rRNA, and 30 tRNA genes. Comparative analysis of the two CP genomes revealed conserved genome structure, gene content, and gene order. However, highly variable regions, sufficient to distinguish between A. polymorpha and L. officinale, were identified in hypothetical chloroplast open reading frame1 (ycf1) and ycf2 genic regions. Nucleotide diversity (Pi) analysis indicated that ycf4⁻chloroplast envelope membrane protein (cemA) intergenic region was highly variable between the two species. Phylogenetic analysis revealed that A. polymorpha and L. officinale were well clustered at family Apiaceae. The ycf4-cemA intergenic region in A. polymorpha carried a 418 bp deletion compared with L. officinale. This region was used for the development of a novel indel marker, LYCE, which successfully discriminated between A. polymorpha and L. officinale accessions. Our results provide important taxonomic and phylogenetic information on herbal medicines and facilitate their authentication using the indel marker.


Assuntos
Angelica/classificação , Genoma de Cloroplastos , Ligusticum/classificação , Sequenciamento Completo do Genoma/métodos , Angelica/genética , Composição de Bases , Cloroplastos/genética , DNA Intergênico , Evolução Molecular , Ordem dos Genes , Tamanho do Genoma , Mutação INDEL , Ligusticum/genética , Fases de Leitura Aberta , Filogenia
12.
Tetrahedron Lett ; 59(49): 4311-4314, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31105351

RESUMO

Two different pathways for the synthesis of annulated pyrido[3,4-b]indoles are reported using metal-catalyzed cyclotrimerization reactions. A stepwise process using Rh(I)-catalysis in the final step of the synthesis and a multicomponent, tandem catalytic approach using Pd(0)-catalysis both lead to complex nitrogen-containing heterocycles in good yields. Substituent effects are investigated for both pathways, demonstrating that the Pd(0)-catalyzed approach is more sensitive to electron- withdrawing groups.

13.
Sensors (Basel) ; 18(11)2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30428593

RESUMO

Prediction of structural deterioration is a challenging task due to various uncertainties and temporal changes in the environmental conditions, measurement noises as well as errors of mathematical models used for predicting the deterioration progress. Monitoring of deterioration progress is also challenging even with successive measurements, especially when only indirect measurements such as structural responses are available. Recent developments of Bayesian filters and Bayesian inversion methods make it possible to address these challenges through probabilistic assimilation of successive measurement data and deterioration progress models. To this end, this paper proposes a new framework to monitor and predict the spatiotemporal progress of structural deterioration using successive, indirect and noisy measurements. The framework adopts particle filter for the purpose of real-time monitoring and prediction of corrosion states and probabilistic inference of uncertain and/or time-varying parameters in the corrosion progress model. In order to infer deterioration states from sparse indirect inspection data, for example structural responses at sensor locations, a Bayesian inversion method is integrated with the particle filter. The dimension of a continuous domain is reduced by the use of basis functions of truncated Karhunen-Loève expansion. The proposed framework is demonstrated and successfully tested by numerical experiments of reinforcement bar and steel plates subject to corrosion.

14.
Sensors (Basel) ; 16(6)2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27258270

RESUMO

Structural health monitoring (SHM) using wireless smart sensors (WSS) has the potential to provide rich information on the state of a structure. However, because of their distributed nature, maintaining highly robust and reliable networks can be challenging. Assessing WSS network communication quality before and after finalizing a deployment is critical to achieve a successful WSS network for SHM purposes. Early studies on WSS network reliability mostly used temporal signal indicators, composed of a smaller number of packets, to assess the network reliability. However, because the WSS networks for SHM purpose often require high data throughput, i.e., a larger number of packets are delivered within the communication, such an approach is not sufficient. Instead, in this study, a model that can assess, probabilistically, the long-term performance of the network is proposed. The proposed model is based on readily-available measured data sets that represent communication quality during high-throughput data transfer. Then, an empirical limit-state function is determined, which is further used to estimate the probability of network communication failure. Monte Carlo simulation is adopted in this paper and applied to a small and a full-bridge wireless networks. By performing the proposed analysis in complex sensor networks, an optimized sensor topology can be achieved.

15.
Bioorg Med Chem Lett ; 24(4): 1188-91, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24461294

RESUMO

Though glycyrrhetinic acid (GA) from Glycyrrhiza glabra was known to exert antioxidant, antifilarial, hepatoprotective, anti-inflammatory and anti-tumor effects, the antitumor mechanism of GA was not clearly elucidated in non-small cell lung cancer cells (NSCLCCs). Thus, in the present study, the underlying apoptotic mechanism of GA was examined in NCI-H460 NSCLCCs. GA significantly suppressed the viability of NCI-H460 and A549 non-small lung cancer cells. Also, GA significantly increased the sub G1 population by cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in a concentration dependent manner in NCI-H460 non-small lung cancer cells. Consistently, GA cleaved poly (ADP-ribosyl) polymerase (PARP), caspase 9/3, attenuated the expression of Bcl-XL, Bcl-2, Cyclin D1 and Cyclin E in NCI-H460 cells. Interestingly, GA attenuated the phosphorylation of protein kinase C (PKC) α/ßII and extracellular activated protein kinase (ERK) as well as activated the phosphorylation of PKC δ and c-Jun NH2-terminal kinase in NCI-H460 cells. Conversely, PKC promoter phorbol 12-myristate 13-acetate (PMA) and JNK inhibitor SP600125 reversed the cleavages of caspase 3 and PARP induced by GA in NCI-H460 cells. Overall, our findings suggest that GA induces apoptosis via inhibition of PKC α/ßII and activation of JNK in NCI-H460 non-small lung cancer cells as a potent anticancer candidate for lung cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácido Glicirretínico/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Humanos , Neoplasias Pulmonares/patologia , Conformação Molecular , Proteína Quinase C beta/antagonistas & inibidores , Proteína Quinase C beta/metabolismo , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
16.
Spinal Cord Ser Cases ; 10(1): 32, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38670974

RESUMO

INTRODUCTION: There are no previously reported cases of locked-in syndrome occurring following cervical spinal surgery. We describe a case of locked-in syndrome following an elective cervical foraminotomy and discuss potential etiologies and contributing factors to our patient's presentation. CASE PRESENTATION: A 54-year-old male with a history of head and neck cancer and prior anterior cervical discectomy and fusion presented with neck pain following a motor vehicle accident. The patient underwent C4-C7 left-sided cervical posterior foraminotomy with no intraoperative complications. On postoperative day 1, the patient suddenly developed rapidly progressing weakness of the extremities and soon became non-verbal. CT angiography and near-infrared spectroscopy confirmed a basilar artery occlusion and left vertebral artery dissection. On MRI, infarcts involving the bilateral pons, left cerebral hemisphere, and left cerebellar infarct were identified. CONCLUSION: The etiology of locked-in syndrome in our patient remains unclear, but it is likely multifactorial. It is possible that the patient was predisposed to vascular injury from prior radiation therapy to the head and neck. In addition, intraoperative vascular insult may have occurred from vibrational shear stress, in turn leading to a vertebral artery dissection, basilar artery occlusion, and pontine infarct, ultimately resulting in our patient's locked-in state.


Assuntos
Vértebras Cervicais , Foraminotomia , Síndrome do Encarceramento , Humanos , Masculino , Pessoa de Meia-Idade , Vértebras Cervicais/cirurgia , Síndrome do Encarceramento/etiologia , Foraminotomia/efeitos adversos , Complicações Pós-Operatórias/etiologia
17.
Cartilage ; : 19476035241233441, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38403983

RESUMO

OBJECTIVE: Marrow stimulation is used to address knee cartilage defects. In this study, we used the fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) to evaluate statistical fragility of outcomes reported in randomized controlled trials (RCTs) evaluating marrow stimulation. DESIGN: PubMed, Embase, and MEDLINE were queried for recent RCTs (January 1, 2010-September 5, 2023) assessing marrow stimulation for cartilage defects of the knee. The FI and rFI were calculated as the number of outcome event reversals required to alter statistical significance for significant and nonsignificant outcomes, respectively. The FQ was determined by dividing the FI by the study sample size. RESULTS: Across 155 total outcomes from 21 RCTs, the median FI was 3 (interquartile range [IQR], 2-5), with an associated median FQ of 0.067 (IQR, 0.033-0.010). Thirty-two outcomes were statistically significant, with a median FI of 2 (IQR, 1-3.25) and FQ of 0.050 (IQR, 0.025-0.069). Ten of the 32 (31.3%) outcomes reported as statistically significant had an FI of 1. In total, 123 outcomes were nonsignificant, with a median rFI of 3 (IQR, 2-5). Studies assessing stem cell augments were the most fragile, with a median FI of 2. In 55.5% of outcomes, the number of patients lost to follow-up was greater than or equal to the FI. CONCLUSION: Statistical findings in RCTs evaluating marrow stimulation for cartilage defects of the knee are statistically fragile. We recommend combined reporting of P-values with FI and FQ metrics to aid in the interpretation of clinical findings in comparative trials assessing cartilage restoration.

18.
Arthroplast Today ; 25: 101285, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38261888

RESUMO

Background: During the initial coronavirus pandemic lockdown period, remote hip and knee arthroplasty care was heavily employed out of necessity. However, data on patient satisfaction with telemedicine specific to hip and knee arthroplasty patients remains unknown. Methods: All patients who had a telemedicine visit in the hip and knee arthroplasty department and completed a telemedicine satisfaction survey at a specialty hospital from April 1, 2020, to December 31, 2020, were identified. Patient satisfaction with telemedicine, gauged through a series of questions, were analyzed and evaluated over time. Independent factors associated with high satisfaction, defined as the "Top Box" response to the survey question "Likelihood of your recommending our video visit service to others," were identified. Results: Overall, 29,003 patients who had an in-person or telemedicine visit in the hip and knee arthroplasty department during the study period were identified. During the initial coronavirus pandemic lockdown period, defined as April 1, 2020-May 31, 2020, rate of overall telemedicine utilization was approximately 84%. After the initial lockdown period, the rate of overall telemedicine utilization was approximately 8% of all visits per month. Average satisfaction scores for a series of 14 questions were consistently above 4.5 out of 5. Multivariable regression revealed younger age, particularly 18-64 years old, to be the only independent factor associated with high satisfaction with telemedicine. The rate of high satisfaction remained statistically similar throughout the study period (P > .05). Conclusions: Patient satisfaction with telemedicine was consistently high in various domains and remained high throughout the study period, regardless of loosened pandemic restrictions. This technology will most likely continue to be utilized, but perhaps it should be targeted at patients younger than 65 years of age.

19.
Spine J ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38301902

RESUMO

BACKGROUND CONTEXT: Racial disparities in spine surgery have been thoroughly documented in the inpatient (IP) setting. However, despite an increasing proportion of procedures being performed as same-day surgeries, whether similar differences have developed in the outpatient (OP) setting remains to be elucidated. PURPOSE: This study aimed to investigate racial differences in postoperative outcomes between Black and White patients following OP and IP lumbar and cervical spine surgery. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Patients who underwent IP or OP microdiscectomy, laminectomy, anterior cervical discectomy and fusion (ACDF), or cervical disc replacement (CDR) between 2017 and 2021. OUTCOME MEASURES: Thirty-day rates of serious and minor adverse events, readmission, reoperation, non-home discharge, and mortality. METHODS: A retrospective review of patients who underwent IP or OP microdiscectomy, laminectomy, anterior cervical discectomy and fusion (ACDF), or cervical disc replacement (CDR) between 2017 and 2021 was conducted using the National Surgical Quality Improvement Program (NSQIP) database. Disparities between Black and White patients in (1) adverse event rates, (2) readmission rates, (3) reoperation rates, (4) non-home discharge rates, (5) mortality rates, (6) operative times, and (7) hospital LOS between Black and White patients were measured and compared between IP and OP surgical settings. Multivariable logistic regression analyses were used to adjust for potential effects of baseline demographic and clinical differences. RESULTS: Of 81,696 total surgeries, 49,351 (60.4%) were performed as IP and 32,345 (39.6%) were performed as OP procedures. White patients accounted for a greater proportion of IP (88.2% vs. 11.8%) and OP (92.7% vs. 7.3%) procedures than Black patients. Following IP surgery, Black patients experienced greater odds of serious (OR 1.214, 95% CI 1.077-1.370, p=.002) and minor adverse events (OR 1.377, 95% CI 1.113-1.705, p=.003), readmission (OR 1.284, 95% CI 1.130-1.459, p<.001), reoperation (OR 1.194, 95% CI 1.013-1.407, p=.035), and non-home discharge (OR 2.304, 95% CI 2.101-2.528, p<.001) after baseline adjustment. Disparities were less prominent in the OP setting, as Black patients exhibited greater odds of readmission (OR 1.341, 95% CI 1.036-1.735, p=0.026) but were no more likely than White patients to experience adverse events, reoperation, individual complications, non-home discharge, or death (p>.050 for all). CONCLUSIONS: Racial inequality in postoperative complications following spine surgery is evident, however disparities in complication rates are relatively less following OP compared to IP procedures. Further work may be beneficial in elucidating the causes of these differences to better understand and mitigate overall racial disparities within the inpatient setting. These decreased differences may also provide promising indication that progress towards reducing inequality is possible as spine care transitions to the OP setting.

20.
Spine Surg Relat Res ; 8(1): 29-34, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38343417

RESUMO

Introduction: While there is anecdotal evidence that the coronavirus disease 2019 (COVID-19) pandemic altered perioperative decision-making in patients requiring posterior cervical fusion (PCF), a national-level analysis to examine the significance of this hypothesis has not yet been conducted. This study aimed to determine the potential differences in perioperative variables and surgical outcomes of PCF performed before vs. during the COVID-19 pandemic. Methods: Adults who underwent PCF were identified in the 2019 (prepandemic) and 2020 (intrapandemic) NSQIP datasets. Differences in 30-day readmission, reoperation, and morbidity were evaluated using multivariate logistic regression. On the other hand, differences in operative time and relative value units (RVUs) were estimated using quantile regression. Furthermore, the odds ratios (OR) for length of stay (LOS) were estimated using negative binomial regression. Secondary outcomes included rates of nonhome discharge and outpatient surgery. Results: A total of 3,444 patients were included in this study (50.7% from 2020). Readmission, reoperation, morbidity, operative time, and RVUs per minute were similar between cohorts (p>0.05). The LOS (OR 1.086, p<0.001) and RVUs-per-case (coefficient +0.360, p=0.037) were significantly greater in 2020 compared to 2019. Operation year 2020 was also associated with lower rates of nonhome discharge (22.3% vs. 25.8%, p=0.017) and higher rates of outpatient surgery (4.8% vs. 3.0%, p=0.006). Conclusions: During the COVID-19 pandemic, a 28% decreased odds of nonhome discharge following PCF and a 72% increased odds of PCF being performed in an outpatient setting were observed. The readmission, reoperation, and morbidity rates remained unchanged during this period. This is notable given that patients in the 2020 group were more frail. This suggests that patients were shifted to outpatient centers possibly to make up for potentially reduced case volume, highlighting the potential to evaluate rehabilitation-discharge criteria. Further research should evaluate these findings in more detail and on a regional basis.

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