RESUMO
AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.
RESUMO
Tricomponent cobalt(salen)-catalyzed carbofunctionalization of unsaturated substrates by radical-polar crossover has the potential to streamline access to broad classes of heteroatom-functionalized synthetic targets, yet the reaction platform has remained elusive, despite the well-developed analogous hydrofunctionalizations mediated by high-valent alkylcobalt intermediates. We report herein the development of a cobalt(salen) catalytic system that enables carbofunctionalization. The reaction entails a tricomponent decarboxylative 1,4-carboamination of dienes and provides a direct route to aromatic allylic amines by obviating preformed allylation reagents and protection of oxidation-sensitive aromatic amines. The catalytic system merges acridine photocatalysis with cobalt(salen)-catalyzed regioselective 1,4-carbofunctionalization that facilitates the crossover of the radical and polar phases of the tricomponent coupling process, revealing critical roles of the reactants, as well as ligand effects and the nature of the formal high-valent alkylcobalt species on the chemo- and regioselectivity.
RESUMO
OBJECTIVE: Selenium (Se) is a key part of the body's oxidation defence system. However, it is unclear whether Se affects the development of aortic aneurysm (AA). An animal experiment was conducted to clarify the role of Se in AA development. METHODS: C57BL/6N male mice were fed with a Se deficient (Se-D, < 0.05 mg/kg), Se adequate (Se-A, 0.2 mg/kg), or Se supplemented (Se-S, 1 mg/kg) diet for 8 weeks. Subsequently, an AA murine model (Se-D, n = 11; Se-A, n = 12; Se-S, n = 15) was established using angiotensin II (Ang II, 1 mg/kg/min) for four weeks plus ß-aminopropionitrile (BAPN, 1 mg/mL) for the first two weeks. Saline replaced Ang II, and BAPN was removed during the modelling process for sham mice (Se-A, n = 9). To determine whether Se deficiency promoted aortic dilation via matrix metalloproteinase-2 (MMP-2), the non-specific MMP inhibitor doxycycline (Dox, 100 mg/kg/day) was given to Se-D AA mice (n = 7) for two weeks. RESULTS: The maximum aortic diameter in Se-D AA model mice was significantly increased compared with Se-A AA model mice. MMP-2 expression and activity in the aortic media of Se-D AA model mice was significantly increased compared with Se-A AA model mice. A large number of vascular smooth muscle cells (VSMCs) were found aggregating in the media of the non-dilated aorta of Se-D AA model mice, which was completely inhibited by Dox. The percentage of VSMCs in aortic media of Se-D AA model mice was significantly higher than in Se-A AA model mice. The maximum aortic diameter and occurrence rate of AA in Se-D AA model mice with Dox were significantly reduced compared with Se-D AA model mice. CONCLUSION: Se deficiency promoted dilatation of the aorta in AA model mice by increasing expression and activity of VSMC derived MMP-2, causing abnormal aggregation and proliferation of VSMCs in aortic media.
Assuntos
Aneurisma Aórtico , Selênio , Masculino , Camundongos , Animais , Metaloproteinase 2 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Dilatação , Selênio/farmacologia , Selênio/metabolismo , Aminopropionitrilo/farmacologia , Camundongos Endogâmicos C57BL , Aorta/metabolismo , Modelos Animais de Doenças , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: The Patented Medicine Prices Review Board (PMPRB), the agency that regulates the prices of patented medicines in Canada, published proposed amendments to the regulatory framework in December 2017. Because of a series of changes and delays, the revised policy has not yet been finalized. We sought to evaluate the potential early impact of the uncertainty about the PMPRB policy on patented-medicine launches. METHODS: We developed a retrospective cohort of patented medicines (molecules) sold in Canada and the 13 countries that the PMPRB currently uses or has proposed to use as price comparators, from sales data from the IQVIA MIDAS database for 2012-2021. The outcome was whether a molecule was launched (i.e., sold) in a specific country within 2 years of its global first launch (2-yr launch). We compared the change of 2-year launch before (2012-2017) and after the proposed amendments were published ("uncertain period," 2018-2021) in Canada with the change in the United States and the other 12 countries as a group ("other-countries group"), using interrupted time series and logistic regressions, respectively. We further conducted analyses for each individual country and subgroups by molecule characteristics, such as therapeutic benefit, separately. RESULTS: We included 242 and 107 new molecules launched before publication of the proposed amendments and during the uncertain period, respectively. The corresponding 2-year launch proportions were 45.0% and 30.8% in Canada, 81.4% and 82.2% in the US, and 83.9% and 70.1% in the other-countries group. All analyses showed changes in 2-year launch during the uncertain period in the US and in the other-countries group that were similar to the changes in Canada. Greater decreases were observed in Norway and Sweden than in Canada. The 2-year launch proportion for molecules with major therapeutic benefit decreased from 45.8% to 31.3% in Canada during the uncertain period and from 87.5% to 62.5% in the other-countries group, but increased from 91.7% to 100% in the US. INTERPRETATION: No negative impact of the PMPRB-policy uncertainty on molecule launches was observed when comparing Canada with price-comparator countries, except for molecules with major therapeutic benefit. The reduction in launches of medicines with major therapeutic benefit in Canada requires continuing investigation.
Assuntos
Custos de Medicamentos , Patentes como Assunto , Canadá , Estudos Retrospectivos , Humanos , Patentes como Assunto/legislação & jurisprudência , Custos de Medicamentos/legislação & jurisprudência , Estados Unidos , Comércio/legislação & jurisprudência , Comércio/economiaRESUMO
BACKGROUND: Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. CASE PRESENTATION: A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. CONCLUSIONS: This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD.
Assuntos
Neuromielite Óptica , Aplasia Pura de Série Vermelha , Humanos , Feminino , Neuromielite Óptica/complicações , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/diagnóstico por imagem , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/complicações , Aplasia Pura de Série Vermelha/diagnóstico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Aquaporina 4/imunologiaRESUMO
OBJECTIVES: To estimate Canadian population norms (health utility values, summary component scores and domain scores) for the VR-12. METHODS: English and French speaking Canadians aged 18 and older completed an online survey that included sociodemographic questions and standardized health status instruments, including the VR-12. Responses to the VR-12 were summarized as: (i) a health utility value; (ii) mental and physical component summary scores (MCS and PCS, respectively), and (iii) eight domain scores. Norms were calculated for the full sample and by gender, age group, and province/territory (univariate), and for several multivariate stratifications (e.g., age group and gender). Results were summarized using descriptive statistics, including number of respondents, mean and standard deviation (SD), median and percentiles (25th and 75th), and minimum and maximum. RESULTS: A total of 6761 people who clicked on the survey link completed the survey (83.4% completion rate), of whom 6741 (99.7%) were included in the analysis. The mean health utility score was 0.698 (SD = 0.216). Mean health utility scores tended to be higher in older age groups, ranging from 0.661 (SD = 0.214) in those aged 18-29 to 0.728 (SD = 0.310) in those aged 80+. Average MCS scores were higher in older age groups, while PCS scores were lower. Females consistently reported lower mean health utility values, summary component scores and domain scores compared with males. CONCLUSIONS: This is the first study to present Canadian norms for the VR-12. Health utility norms can serve as a valuable input for Canadian economic models, while summary component and domain norms can help interpret routinely-collected data.
Assuntos
População Norte-Americana , Qualidade de Vida , Realidade Virtual , Idoso , Feminino , Humanos , Masculino , Canadá , Nível de Saúde , Qualidade de Vida/psicologia , Inquéritos e Questionários , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
The regulatory role of N(6)-methyladenosine (m(6)A) and its nuclear binding protein YTHDC1 in pre-mRNA splicing remains an enigma. Here we show that YTHDC1 promotes exon inclusion in targeted mRNAs through recruiting pre-mRNA splicing factor SRSF3 (SRp20) while blocking SRSF10 (SRp38) mRNA binding. Transcriptome assay with PAR-CLIP-seq analysis revealed that YTHDC1-regulated exon-inclusion patterns were similar to those of SRSF3 but opposite of SRSF10. In vitro pull-down assay illustrated a competitive binding of SRSF3 and SRSF10 to YTHDC1. Moreover, YTHDC1 facilitates SRSF3 but represses SRSF10 in their nuclear speckle localization, RNA-binding affinity, and associated splicing events, dysregulation of which, as the result of YTHDC1 depletion, can be restored by reconstitution with wild-type, but not m(6)A-binding-defective, YTHDC1. Our findings provide the direct evidence that m(6)A reader YTHDC1 regulates mRNA splicing through recruiting and modulating pre-mRNA splicing factors for their access to the binding regions of targeted mRNAs.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Sítios de Ligação , Éxons , Células HeLa , Humanos , Fatores de Processamento de RNA , RNA Mensageiro/metabolismo , Fatores de Processamento de Serina-ArgininaRESUMO
Solute carrier (SLC) transporters play a dual role in the occurrence and progression of tumours by acting as both suppressors and promoters. However, the overall impact of SLC transcriptome signatures on the tumour microenvironment, biological behaviour and clinical stratification of gastric cancer has not been thoroughly investigated. Therefore, we comprehensively analysed the expression profiles of the SLC transporter family members to identify novel molecular subtypes in gastric cancer. We identified two distinct SLC subtypes, SLC-S1 and SLC-S2, using non-negative matrix factorization. These subtypes were markedly linked with the tumour microenvironment landscape, biological pathway activation and distinct clinical features of gastric cancer. Furthermore, a new scoring model, the SLC score, was developed to quantify the SLC subtypes. High SLC scores indicated a pattern of 'SLC-S2', characterized by stromal infiltration and activation, poor prognosis and insensitivity to chemotherapy and immunotherapy, but high sensitivity to imatinib. The SLC score could serve as a supplement to the Tumour Node Metastasis (TNM) staging system to guide personalized treatment strategies and predict prognosis for patients with gastric cancer.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Proteínas de Membrana Transportadoras/metabolismo , Transporte Biológico , Imunoterapia , Microambiente Tumoral/genéticaRESUMO
HB (hepatoblastoma) is most common in children with liver cancer and few options for treating HB. Thus, it is of great significance to investigate the regulatory mechanism of HB and/or identify new therapeutic targets for clinical treatment of HB. Here, we showed that ACLY (ATP citrate lyase), an important lipometabolic enzyme for de novo biosynthesis of fatty acids and steroids, has a higher expression in HB tissues than noncancerous tissues, and is required for HB cell proliferation. Moreover, knocking down ACLY in HB cells caused severe S-phase arrest and apoptosis. Mechanistically, ACLY knockdown significantly silenced the Wnt signaling pathway and reduced ß-catenin expression in HB cells. Conversely, the apoptotic alleviation of HB cells by overexpressing ACLY was blocked by silencing ß-catenin, suggesting the modulation of HB cells by ACLY-ß-catenin axis. Our results uncovered the role of ACLY in HB cells and presented a theoretical approach for HB targeted therapy in the future.
Assuntos
Hepatoblastoma , Neoplasias Hepáticas , Criança , Humanos , Hepatoblastoma/genética , beta Catenina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , ATP Citrato (pro-S)-Liase/metabolismoRESUMO
Cyano-bridged 4d-4f molecular nanomagnets have re-called increasing research interests in molecular magnetism since they offer more possibilities in achieving novel nanomagnets with versatile structures and magnetic interactions. In this work, four ß-diketone ligands bearing different substitution N-sites were designed and synthesized, namely 1-(2-pyridyl)-3-(3-pyridyl)-1,3-propanedione (HL1 ), 1,3-Bis (3-pyridyl)-1,3-propanedione (HL2 ), 1-(4-pyridyl)-3-(3-pyridyl)-1,3-propanedione (HL3 ), and 1,3-Bis (4-pyridyl)-1,3-propanedione (HL4 ), to tune the magnetic relaxation behaviors of cyano-bridged {DyIII MoV } systems. By reacting with DyCl3 â 6H2 O and K4 Mo(CN)8 â 2H2 O, four cyano-bridged complexes, namely {[Dy[MoV (CN)8 ](HL1 )2 (H2 O)3 ]} â 6H2 O (1), {[Dy[MoV (CN)8 ](HL2 )(H2 O)3 (CH3 OH)]}2 â 2CH3 OH â 3H2 O (2), {[Dy[MoV (CN)8 ](HL3 )(H2 O)2 (CH3 OH)] â H2 O}n (3), and {[Dy[MoV (CN)8 ](HL4 )2 (H2 O)3 ]} â 2H2 Oâ CH3 OH (4) were obtained. Structural analyses revealed that 1 and 4 are binuclear complexes, 2 has a tetragonal structure, and 3 exhibits a stair-like polymer chain structure. The DyIII ions in all complexes have eight-coordinated configurations with the coordination spheres DyO7 N1 for 1 and 4, DyO6 N2 for 2, and DyO5 N3 for 3. Magnetic measurements indicate that 1 is a zero-field single-molecule magnet (SMM) and complexes 2-4 are field-induced SMMs, with complex 4 featuring a two-step relaxation process. The magnetic characterizations and ab initio calculations revealed that changing the N-sites in the ß-diketone ligands can effectively alter the structures and magnetic properties of cyano-bridged 4d-4f nanomagnets by adjusting the coordination environments of the DyIII centers.
RESUMO
BACKGROUND: Uridyl peptide compounds are renowned as a subclass of nucleoside antibiotics for their highly specific antibacterial activity against Gram-negative bacteria and the unique target of action. We previously activated the biosynthetic gene cluster of a uridyl peptide antibiotic, mureidomycin, in Streptomyces roseosporus NRRL 15998 by introducing an exogenous positive regulator gene ssaA, and the generated strain was designated as Sr-hA. This study aims to further explore mureidomycin analogs from Sr-hA as well as the collaborative roles of two wide-spread genes, SSGG-02980 and SSGG-03002 encoding putative nuclease/phosphatase and oxidoreductase respectively, in mureidomycin diversification. RESULTS: In order to understand how SSGG-02980 and SSGG-03002 contribute to mureidomycin biosynthesis, the gene disruption mutants and complementary strains were constructed. Mass spectrometry analyses revealed that two series of pairwise mureidomycin analogs were synthesized in Sr-hA with a two-dalton difference in molecular weight for each pair. By disruption of SSGG-03002, only mureidomycins with lower molecular weight (MRDs, 1-6) could be specifically accumulated in the mutant (∆03002-hA), whereas the other series of products with molecular weight plus 2 Da (rMRDs, 1'-6') became dominant in SSGG-02980 disruption mutant (∆02980-hA). Further comprehensive NMR analyses were performed to elucidate the structures, and three MRDs (3, 4, 5) with unsaturated double bond at C5-C6 of uracil group were characterized from ∆03002-hA. In contrast, the paired rMRDs analogs (3', 4', 5') from ∆SSGG-02980 corresponding to 3, 4 and 5 were shown to contain a single bond at this position. The results verified that SSGG-03002 participates in the reduction of uracil ring, whereas SSGG-02980 antagonizes the effect of SSGG-03002, which has been rarely recognized for a phosphatase. CONCLUSIONS: Overall, this study revealed the key roles of two wide-spread families of enzymes in Streptomyces. Of them, oxidoreductase, SSGG-03002, is involved in dihydro-mureidomycin biosynthesis of S. roseosporus, whereas nuclease/phosphatase, SSGG-02980, has an adverse effect on SSGG-03002. This kind of unusual regulation model between nuclease/phosphatase and oxidoreductase is unprecedented, providing new insights into the biosynthesis of mureidomycins in Streptomyces. The findings would be of significance for structural diversification of more uridyl peptide antibiotics against Gram-negative bacteria.
Assuntos
Antibacterianos , Streptomyces , Peptídeos/metabolismo , Proteínas de Bactérias/metabolismo , Streptomyces/metabolismo , Oxirredutases/metabolismo , Uracila/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Família MultigênicaRESUMO
OBJECTIVES: This study aimed to conduct a scoping review of randomized controlled trials (RCTs) and investigate which work productivity loss outcomes were measured in these RCTs, how each outcome was measured and analyzed, and how the results for each outcome were presented. METHODS: A systematic search was conducted from January 2010 to April 2020 from 2 databases: PubMed and Cochrane Central Register of Controlled Trials. Data on country, study population, disease focus, sample size, work productivity loss outcomes measured (absenteeism, presenteeism, employment status changes), and methods used to measure, report, and analyze each work productivity loss outcome were extracted and analyzed. RESULTS: We found 435 studies measuring absenteeism or presenteeism, of which 155 studies (35.6%) measured both absenteeism and presenteeism and were included in our final review. Only 9 studies also measured employment status changes. The most used questionnaire was the Work Productivity and Activity Impairment Questionnaire. The analysis of absenteeism and presenteeism data was mostly done using regression models (n = 98, n = 98, respectively) for which a normal distribution was assumed (n = 77, n = 89, respectively). Absenteeism results were most often presented in time whereas presenteeism was commonly presented using a percent scale or score. CONCLUSIONS: There is a lack of consensus on how to measure, analyze, and present work productivity loss outcomes in RCTs published in the past 10 years. The diversity of measurement, analysis, and presentation methods used in RCTs may make comparability challenging. There is a need for guidelines providing recommendations to standardize the comprehensiveness and the appropriateness of methods used to measure, analyze, and report work productivity loss in RCTs.
Assuntos
Eficiência , Emprego , Humanos , Absenteísmo , Presenteísmo , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Catheter-associated urinary tract infection (CAUTI) ranks second among nosocomial infections in elderly patients after lung infections. Improper treatment can lead to death. This study analysed the risk factors, pathogen distribution, clinical characteristics and outcomes of CAUTI in elderly inpatients with a large sample size to provide evidence for clinical prevention and control. METHODS: Based on the HIS and LIS, a caseâcontrol study was conducted on all hospitalized patients with indwelling urinary catheters ≥ 60 years old from January 1, 2019, to December 31, 2022, and the patients were divided into the CAUTI group and the non-CAUTI group. RESULTS: CAUTI occurred in 182 of 7295 patients, and the infection rate was 3.4/per 1000 catheter days. Urine pH ≥ 6.5, moderate dependence or severe dependence in the classification of self-care ability, age ≥ 74 years, male sex, hospitalization ≥ 14 days, indwelling urinary catheter ≥ 10 days, diabetes and malnutrition were independent risk factors for CAUTI (P < 0.05). A total of 276 strains of pathogenic bacteria were detected in urine samples of 182 CAUTI patients at different times during hospitalization. The main pathogens were gram-negative bacteria (n = 132, 47.83%), followed by gram-positive bacteria (n = 91, 32.97%) and fungi (n = 53, 19.20%). Fever, abnormal procalcitonin, positive urinary nitrite and abnormal urination function were the clinical characteristics of elderly CAUTI patients (P < 0.001). Once CAUTI occurred in elderly patients, the hospitalization days were increased by 18 days, the total hospitalization cost increased by ¥18,000, and discharge all-cause mortality increased by 2.314 times (P<0.001). CONCLUSION: The situation of CAUTI in the elderly is not optimistic, it is easy to have a one-person multi-pathogen infection, and the proportion of fungi infection is not low. Urine pH ≥ 6.5, moderate or severe dependence on others and malnutrition were rare risk factors for elderly CAUTI in previous studies. Our study analysed the clinical characteristics of CAUTI in the elderly through a large sample size, which provided a reliable basis for its diagnosis and identified the adverse outcome of CAUTI.
Assuntos
Infecções Relacionadas a Cateter , Infecção Hospitalar , Desnutrição , Infecções Urinárias , Humanos , Masculino , Idoso , Pessoa de Meia-Idade , Cateterismo Urinário/efeitos adversos , Infecções Relacionadas a Cateter/prevenção & controle , Estudos de Casos e Controles , Infecções Urinárias/etiologia , Infecções Urinárias/microbiologia , Infecção Hospitalar/etiologia , Infecção Hospitalar/microbiologia , Cateteres de Demora/microbiologia , Cateteres Urinários/efeitos adversos , Desnutrição/complicaçõesRESUMO
INTRODUCTION: Typewriter tinnitus refers to a special kind of staccato tinnitus, which is mostly described by patients as Morse code, popcorn, or machine-gun. It has been accepted that the mechanism of typewriter tinnitus is caused by the neurovascular compression of the cochleovestibular nerve. Patients who suffered from typewriter tinnitus have exhibited a good response to carbamazepine or oxcarbazepine, but there is a risk of recurrence after treatment cessation. The present study aims to determine the value of auditory brainstem response (ABR) in diagnosing typewriter tinnitus and predicting relapse after drug withdrawal. METHODS: Patients who presented with typewriter tinnitus from March 2019 to March 2022 were included for the present retrospective study. The auditory and vestibular test results and drug treatment effects were collected and analyzed. Patients with idiopathic unilateral subjective tinnitus, who were matched by age to patients with typewriter tinnitus at a ratio of 2:1, were consecutively recruited for the control group. RESULTS: Eighteen patients with typewriter tinnitus and 38 controls were included. Ears with typewriter tinnitus had longer interpeak latency (IPL) I-III, and wave III and V latencies, and a higher ratio of IPL I-III ≥2.3 ms based on ABR, when compared to the unaffected side and controls ( p <0.05). Seventeen patients with typewriter tinnitus responded positively to medication. Among these patients, seven patients had a relapse after drug cessation, while 10 patients did not have a relapse. The relapse group had significantly longer IPL I-III and wave V latency, older age, and poorer hearing, when compared to the nonrelapse group ( p < 0.05). Furthermore, IPL I-III had the largest area under the receiver operating characteristic curve, and the optimal cutoff was 2.4 ms (sensitivity, 100.0%; specificity, 66.7%). There were no significant differences in other demography or other clinical test results between the relapse and nonrelapse groups ( p > 0.05). Ramsay Hunt syndrome and neuromyelitis optica spectrum disorders were identified in two cases. CONCLUSION: Prolonged IPL I-III based on ABR can help in the diagnosis of typewriter tinnitus and its prognosis after treatment cessation. Patients with IPL I-III greater than 2.4 ms, older age and poorer hearing are more likely to relapse. In addition to the neurovascular conflict of the cochleovestibular nerve, the etiologies of neuroinflammation and demyelinating diseases are also possible for typewriter tinnitus.
Assuntos
Zumbido , Humanos , Zumbido/diagnóstico , Zumbido/etiologia , Estudos Retrospectivos , Prognóstico , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , RecidivaRESUMO
PURPOSE: To analyze and stratify the possible risk factors of venous thromboembolism (VTE) in lateral skull base surgery (LSBS) using the Caprini risk assessment model. METHODS: In a single center, a retrospective study was conducted with patients who underwent LSBS from June 2016 to August 2021. The clinical characteristics and blood chemistry tests were collected. The incidence of VTE within 30 days of surgery was recorded. The Caprini risk score was calculated to assess the postoperative VTE risk. RESULTS: Among the 123 patients in this study, the VTE incidence within 30 postoperative days was 8.9%. The total Caprini risk score in VTE patients (5.6 ± 1.9 points) was significantly higher than that of non-VTE patients (4.6 ± 1.4 points; p = 0.028). The binary logistic regression showed the total Caprini score as the only independent indicator of postoperative VTE. The receiver operating characteristic curve analysis showed that the Caprini score at 6.5 points had low sensitivity (36.4%) but high specificity (91.1%), with the largest area under the curve being 0.659. The VTE rate was significantly higher in patients with a total Caprini score ≥ 7 points (28.6%) compared to those with a total Caprini score ≤ 6 points (7.3%; p = 0.022). CONCLUSION: LSBS patients have a high risk of developing postoperative VTE. Patients with a Caprini score ≥ 7 points had a significantly higher risk of developing VTE after LSBS. The Caprini risk system was useful in assessing the VTE risk in LSBS. However, more data, calibration, and validation are necessary to establish an exclusive Caprini risk system for LSBS.
Assuntos
Embolia Pulmonar , Base do Crânio , Tromboembolia Venosa , Humanos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Base do Crânio/cirurgia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Complicações Pós-OperatóriasRESUMO
Colossal and anisotropic thermal expansion is a key function for microscale or nanoscale actuators in material science. Herein, we present a hexanuclear compound of [(Tp*)FeIII (CN)3 ]4 [FeII (Ppmp)]2 â 2 CH3 OH (1, Tp*=hydrotris(3,5-dimethyl-pyrazol-1-yl)borate and Ppmp=2-[3-(2'-pyridyl)pyrazol-1-ylmethyl]pyridine), which has a rhombic core structure abbreviated as {FeIII 2 FeII 2 }. Magnetic susceptibility measurements and single-crystal X-ray diffraction analyses revealed that 1 underwent thermally-induced spin transition with the thermal hysteresis. The FeII site in 1 behaved as a spin crossover (SCO) unit, and significant deformation of its octahedron was observed during the spin transition process. Moreover, the distortion of the FeII centers actuated anisotropic deformation of the rhombic {FeIII 2 FeII 2 } core, which was spread over the whole crystal through the subsequent molecular rearrangements, leading to the colossal anisotropic thermal expansion. Our results provide a rational strategy for realizing the colossal anisotropic thermal expansion and shape memory effects by tuning the magnetic bistability.
RESUMO
To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
Assuntos
Biomarcadores Tumorais/genética , Metotrexato/uso terapêutico , Mutagênese/efeitos dos fármacos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , 5'-Nucleotidase/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Receptores de Glucocorticoides/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Increasing evidence has shown that noise overexposure could lead to impaired hippocampal function. Hippocampal alteration is also observed in several auditory deficits, including hearing loss, and tinnitus. Therefore, the functions of hearing and cognition interact with each other. Here, we summarize the evidence that noise affects the hippocampus from aspects of behavior, neurogenesis, ultrastructure, neurotransmission, other biomarkers, and electrophysiology. We also address hippocampal alterations in auditory disorders, including hearing loss and tinnitus. Based on the current state of the field, we point out several aspects that need further investigation. This review is not only to provide a comprehensive summary of the current state of the field but to emphasize that hearing matters in cognition and pave the way for future research.
Assuntos
Vias Auditivas , Zumbido , Vias Auditivas/metabolismo , Hipocampo/metabolismo , Humanos , Neurogênese , Ruído , Zumbido/metabolismoRESUMO
BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common intensive care unit (ICU)-acquired infections, which can cause multiple adverse events. Due to bacterial mutation and overuse of antimicrobial drugs, multidrug-resistant organisms (MDRO) has become one of the major causes of postoperative VAP infections in cardiac patients. Therefore, this study aims to explore the risk factors for VAP with MDRO following cardiac surgery in adults. METHODS: The clinical data of adult VAP patients following cardiac surgery in the hospital from Jan 2017 to May 2021 were analyzed retrospectively, and the patients were divided into the MDRO VAP group and the non-MDRO VAP group. Univariable and multivariable logistic regression analyses were performed on risk factors in patients with MDRO VAP. The species and drug sensitivity of pathogens isolated from the VAP patients were also analyzed. RESULTS: A total of 61 VAP cases were involved in this study, with 34 cases in the MDRO VAP group (55.7%) and 27 cases in the non-MDRO VAP group (44.3%). Multivariable logistic regression analysis showed that independent risk factors for MDRO VAP included preoperative creatinine clearance rate (CCR) ≥ 86.6ml, intraoperative cardiopulmonary bypass (CPB) time ≥ 151 min, postoperative acute kidney injury (AKI) and nasal feeding. Gram-negative bacilli were the main pathogens in VAP patients (n = 54, 90.0%), with the highest rate of Acinetobacter baumannii (n = 24, 40.0%). Additionally, patients with MDRO VAP had a significantly longer postoperative intensive care unit (ICU) duration and higher hospitalization costs than non-MDRO VAP patients, but there was no notable difference in the 28-day mortality rate between the two groups. CONCLUSION: Based on implementing measures to prevent VAP, clinicians should pay more attention to patients with kidney disease, longer intraoperative CPB time, and postoperative nasal feeding to avoid MDRO infections.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Pneumonia Associada à Ventilação Mecânica , Adulto , Humanos , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/etiologia , Estudos Retrospectivos , Unidades de Terapia Intensiva , Fatores de Risco , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Antibacterianos/uso terapêuticoRESUMO
PURPOSE: To investigate the clinical value of electrophysiological tests in indicating pathogenic vascular contact of the 8th nerve in definite vestibular paroxysmia (VP) cases to provide a reference for decompression surgery. METHODS: We retrospectively analyzed patients who had vertigo, unilateral tinnitus, or hearing loss and exhibited vascular contact of the 8th cranial nerve by MRI. Participants were classified into the VP or non-VP group according to the criteria of the Bárány Society in 2016. The demographic characteristics and audiological and electrophysiological test results of the two groups were compared. Receiver operating characteristic (ROC) curves were calculated for ABR to determine the best parameters and cutoff values to predict the existence of pathological neurovascular contact in VP. RESULTS: Thirteen patients in the VP group and 66 patients in the non-VP group were included. VP patients had longer interpeak latency (IPL) I-III and wave III latency compared to non-VP patients (p < 0.001; p < 0.001). According to the ROC analyses, IPL I-III and wave III latency were the best indicators for the diagnosis of VP. The optimal cutoff for IPL I-III was 2.3 ms (sensitivity 84.6%, specificity 95.5%), and that for wave III latency was 4.0 ms (sensitivity 92.3%, specificity 77.3%). There were no differences in the PTA, caloric test, o-VEMP, or c-VEMP results between the two groups. CONCLUSION: Prolonged IPL I-III and the wave III latency of ABR strongly suggested that vascular contact of the 8th cranial nerve was pathological, which may provide some references for microvascular decompression surgery of VP.