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1.
BMC Med Res Methodol ; 23(1): 5, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611147

RESUMO

BACKGROUND: In the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease without intervention. METHODS: This paper studies the generalized landmark analysis (GLA), a statistical framework to develop prediction models for longitudinal data. The GLA includes the LA as a special case, and generalizes it to situations where the baseline is not a risk-changing clinical milestone with a more useful interpretation. Unlike the LA, the landmark variable does not have to be time since baseline in the GLA, but can be any time-varying prognostic variable. The GLA can also be viewed as a longitudinal generalization of localized prediction, which has been studied in the context of low-dimensional cross-sectional data. We studied the GLA using data from the Chronic Renal Insufficiency Cohort (CRIC) Study and the Wisconsin Allograft Replacement Database (WisARD) and compared the prediction performance of SPM and GLA. RESULTS: In various validation populations from longitudinal data, the GLA generally had similarly or better predictive performance than SPM, with notable improvement being seen when the validation population deviated from the baseline population. The GLA also demonstrated similar or better predictive performance than LA, due to its more general model specification. CONCLUSIONS: GLA is a generalization of the LA such that the landmark variable does not have to be the time since baseline. It has better interpretation when the baseline is not a risk-changing clinical milestone. The GLA is more adaptive to the validation population than SPM and is more flexible than LA, which may help produce more accurate prediction.


Assuntos
Estudos Transversais , Humanos , Prognóstico , Estudos Longitudinais , Fatores de Risco
2.
World J Emerg Med ; 14(1): 25-30, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36713350

RESUMO

BACKGROUND: To investigate the most appropriate dual antiplatelet therapy (DAPT) duration for patients with acute coronary syndrome (ACS) after drug-eluting stent (DES) implantation in the largest cardiovascular center of China. METHODS: We enrolled 5,187 consecutive patients with ACS who received DES from January to December 2013. Patients were divided into four groups based on DAPT duration: standard DAPT group (11-13 months, n=1,568) and prolonged DAPT groups (13-18 months [n=308], 18-24 months [n=2,125], and >24 months [n=1,186]). Baseline characteristics and 5-year clinical outcomes were recorded. RESULTS: Baseline characteristics were similar across the four groups. Among the four groups, those with prolonged DAPT (18-24 months) had the lowest incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (14.1% vs. 11.7% vs. 9.6% vs. 24.2%, P<0.001), all-cause death (4.8% vs. 3.9% vs. 2.1% vs. 2.6%, P<0.001), cardiac death (3.1% vs. 2.6% vs. 1.4% vs. 1.9%, P=0.004), and myocardial infarction (MI) (3.8% vs. 4.2% vs. 2.5% vs. 5.8%, P<0.001). The incidence of bleeding was not different among the four groups (9.9% vs. 9.4% vs. 11.0% vs. 9.4%, P=0.449). Cox multivariable analysis showed that prolonged DAPT (18-24 months) was an independent protective factor for MACCEs (hazard ratio [HR] 0.802, 95% confidence interval [CI] 0.729-0.882, P<0.001), all-cause death (HR 0.660, 95% CI 0.547-0.795, P<0.001), cardiac death (HR 0.663, 95% CI 0.526-0.835, P<0.001), MI (HR 0.796, 95% CI 0.662-0.957, P=0.015), and target vessel revascularization (HR 0.867, 95% CI 0.755-0.996, P=0.044). Subgroup analysis for high bleeding risk showed that prolonged DAPT remained an independent protective factor for all-cause death and MACCEs. CONCLUSION: For patients with ACS after DES, appropriately prolonging the DAPT duration may be associated with a reduced risk of adverse ischemic events without increasing the bleeding risk.

3.
Physiol Plant ; : e13851, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631431

RESUMO

Anthocyanins widely exist in plants and they are important pigments for color of petals and fruits. They are produced through a multi-step pathway controlled by transcription factor complexes. The anthocyanin skeleton modification is the last reaction in the anthocyanin synthesis pathway, which improves the stability of anthocyanins. Acylation modification is an important modification of anthocyanins. However, the identification and function of anthocyanin acyltransferase genes and their expression regulation are rarely reported. In this study, we identified the petunia anthocyanin acyltransferase gene, PhAAT1. PhAAT1 is located in the cytoplasm and PhAAT1 silencing changed flower color and reduced the stability of anthocyanin. Metabolomics analysis showed that PhAAT1 silencing led to the reduction of p-coumaroylated and caffeoylated anthocyanins. In addition, PhAAT1 was positively regulated by the MYB transcription factor, PhAN2, which directly interacts with the promoter of PhAAT1.

4.
Clin Chim Acta ; 540: 117217, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36610466

RESUMO

BACKGROUND: It is well established that lipoprotein(a)[Lp(a)] and low-density lipoprotein cholesterol (LDL-C) play a vital role in atherosclerosis. We investigated the prevalence and prognostic implications of increased Lp(a) in patients undergoing percutaneous coronary intervention (PCI) according to different LDL-C concentrations. METHODS: A total of 9,190 patients with CAD after PCI were consecutively enrolled in the study and subsequently divided into three groups according to baseline LDL-C at cut-off of 70 and 100 mg/dl. Increased Lp(a) was defined as > 30 mg/dl. The primary endpoint was all-cause death. Second endpoint was cardiac death. Cox regression, Kaplan-Meier and Sensitivity analysis were performed. RESULTS: During an average of 5.0 y of follow-up, 354 (3.9 %) patients experienced all-cause death with 213(2.3 %) of whom from cardiac death. Increased Lp(a) was present in 25.7 %, 34.2 %, and 40.6 % across the LDL-C < 70, 70-100 and≧100 mg/dl groups, respectively. After multivariate adjustment, Lp(a) elevation remained significantly associated with 5-y all-cause death (adjusted HR, 1.243; 95 % CI 1.001-1.544; p = 0.048) in the total cohort and only in those with LDL-C ≥ 100 mg/dl (adjusted HR, 1.642; 95 % CI 1.139-2.367; p = 0.008) when analyzed within each LDL-C category. Consistently with the results of associations between Lp(a) and cardiac death (adjusted HR, 1.534; 95 % CI 1.164-2.021; p = 0.002 for total cohort and adjusted HR, 2.404; 95 % CI 1.439-3.872; p < 0.001 for LDL-C ≥ 100 mg/dl). And this relationship holds after adjusting for LDL-Ccorr additionally. These findings are confirmed again in sensitivity analyses that excluded patients with Lp(a) concentrations in the top or the bottom 5 %. CONCLUSIONS: We confirmed that increased Lp(a) was associated with increased risk of long-term outcomes, and such an association was modified by the baseline LDL-C concentrations. Screening of high Lp(a) in individuals with elevations of LDL-C may enables risk stratification for poor prognosis.

5.
Drug Resist Updat ; 67: 100926, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36682222

RESUMO

AIMS: Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance. METHODS: By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma. RESULTS: FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients. CONCLUSION: Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.

6.
J Cardiothorac Surg ; 18(1): 29, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647165

RESUMO

BACKGROUND: Azygos vein aneurysms (AVAs) are extremely rare. The majority of patients have no obvious clinical symptoms, so they are found by physical examination or by chance. There is limited clinical treatment experience that can be referred to, and there are no clear guidelines or research evidence standardizing the surgical and interventional therapy. Here, we report a patient with idiopathic AVA whose three-dimensional reconstruction of the tumor was completed before surgery. On the basis of three-dimensional reconstruction, single-port thoracoscopic resection of the AVA was successfully completed and reported for the first time. The previously reported cases are summarized to provide guidance for the diagnosis and treatment of patients with AVAs. CASE PRESENTATION: A 56-year-old man was transferred to our hospital due to "dysphagia". The diagnosis of AVA was made after enhanced computed tomography, gastroscopy, fiberoptic bronchoscopy, and three-dimensional reconstruction. Congenital weakness or degenerative changes causes the vein walls to be extremely thin that the AVA had the risk of ruptur. Furthermore, the patient had symptoms of dysphagia, he received single-port thoracoscopic surgery. After the operation, his dysphagia disappeared. The postoperative pathology confirmed hemangioma. The patient was discharged 3 days after surgery without any complications. CONCLUSIONS: AVAs are rare. Preoperative three-dimensional reconstruction can greatly help surgeons clarify the disease diagnosis, formulate the surgical plan, avoid damage to the surrounding vital organs, and reduce intraoperative bleeding. Thoracoscopic surgery to remove AVAs is difficult and has a high risk of bleeding, while more minimally invasive single-port thoracoscopic surgery is also safe and effective for the treatment of AVAs.


Assuntos
Aneurisma , Veia Ázigos , Masculino , Humanos , Pessoa de Meia-Idade , Veia Ázigos/cirurgia , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Toracoscopia , Tomografia Computadorizada por Raios X , Broncoscopia
7.
Gastrointest Endosc ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36657608

RESUMO

BACKGROUND AND AIMS: Treatment strategies for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with esophagogastric varices (EGV) are complicated and risky. We aimed to assess the efficacy and safety of endoscopic submucosal dissection (ESD) in the treatment of such patients and explore optimal treatment strategies. METHODS: We retrospectively enrolled 15 cirrhotic patients with EGV who underwent ESD for early cancers or precancerous lesions of the upper gastrointestinal tract from January 2012 to December 2021 at our center. Clinical features, endoscopic findings, treatment methods, adverse events and follow-up data were analyzed. RESULTS: Of the 15 patients, 1 had a platelet count <30×1000/mm3. Five were untreated for EGV, 1 was treated after ESD, 6 were treated before ESD, 1 was treated before and during ESD, and 2 were treated during ESD. The R0 resection rate was 100%. Of the 16 mucosal lesions, 15 were ERB-0 or ERB-c1, and 1 was ERB-c2. No patient experienced deterioration in liver function. The only adverse events were fever in 2 patients and postoperative bleeding (PB) in 2 patients. During a median follow-up of 27 months, 1 patient's esophageal HGD recurred at 19 months. No death resulted from the ESD procedure, liver function injury or gastrointestinal tumor itself. CONCLUSION: ESD is an effective and safe treatment for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with EGV. The incidence of severe adverse events is very low due to the development of individualized clinical treatment strategies.

8.
J Chem Theory Comput ; 19(1): 25-32, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36508260

RESUMO

We demonstrate the use of Googles cloud-based Tensor Processing Units (TPUs) to accelerate and scale up conventional (cubic-scaling) density functional theory (DFT) calculations. Utilizing 512 TPU cores, we accomplish the largest such DFT computation to date, with 247848 orbitals, corresponding to a cluster of 10327 water molecules with 103270 electrons, all treated explicitly. Our work thus paves the way toward accessible and systematic use of conventional DFT, free of any system-specific constraints, at unprecedented scales.

9.
J Org Chem ; 88(1): 690-700, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36485009

RESUMO

A variety of tetrahydro-5H-indolo[2,3-b]quinolines were prepared in 40-97% yields through a copper(II)-catalyzed cascade reaction of aza-o-quinone methides generated in situ from 2-(chloromethyl)anilines and indoles. Experimental results showed that the reaction underwent double 1,4-additions and sequential intramolecular cyclization. The present method features broad substrate scope, good functional group tolerance, and easy gram scalable preparation of indolo[2,3-b]quinolines.


Assuntos
Indóis , Quinolinas , Indóis/química , Estrutura Molecular , Cobre/química , Quinolinas/química , Catálise
10.
J Clin Oncol ; : JCO2201490, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36473145

RESUMO

PURPOSE: Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1-expressing ESCC remains debatable. METHODS: Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS: The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1-expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1-expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION: This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.

11.
J Med Internet Res ; 24(12): e40341, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459398

RESUMO

BACKGROUND: In a rapidly digitalizing world, the inability of older adults to leverage digital technology has been associated with weaker social connections and poorer health outcomes. Despite the widespread digital adoption in Singapore, older adults, especially those of lower socioeconomic status (SES), still face difficulties in adopting information and communications technology and are typically digitally excluded. OBJECTIVE: We aimed to examine the impact of the volunteer-led, one-on-one, and home-based digital literacy program on digital literacy and health-related outcomes such as self-reported loneliness, social connectedness, quality of life, and well-being for older adults of low SES. METHODS: A nonrandomized controlled study was carried out in Singapore between July 2020 and November 2021 involving 138 digitally excluded community-dwelling older adults aged ≥55 years and of lower SES. Older adults awaiting participation in the program served as controls. Older adults under the intervention were equipped with a smartphone and cellular data, underwent fortnightly to monthly digital literacy training with volunteers to learn digital skills, and digitally connected to their existing social networks. Primary outcome was the improvement in self-reported digital literacy. Secondary outcomes included improvements in University of California, Los Angeles 3-item loneliness scale, Lubben Social Network Scale-6, EQ-5D-3L and EQ visual analogue scale scores, and Personal Wellbeing Score. RESULTS: There were significant improvements in digital literacy scores in the intervention group as compared to controls (mean difference 2.28, 95% CI 1.37-3.20; P<.001). Through multiple linear regression analyses, this difference in digital literacy scores remained independently associated with group membership after adjusting for differences in baseline scores, age, gender, education, living arrangement, housing type, and baseline social connectivity and loneliness status. There was no statistically significant difference in University of California, Los Angeles 3-item loneliness scale, Lubben Social Network Scale-6, Personal Wellbeing Score, or EQ-5D Utility and visual analogue scale score. CONCLUSIONS: This study adds to the growing research on digital inclusion by showing that a volunteer-led, one-on-one, and home-based digital literacy program contributed to increase digital literacy in older adults of low SES. Future studies should look into developing more older adult-friendly digital spaces and technology design to encourage continued digital adoption in older adults and, eventually, impact health-related outcomes.


Assuntos
Alfabetização , Qualidade de Vida , Humanos , Idoso , Singapura , Renda , Classe Social
12.
Invest Ophthalmol Vis Sci ; 63(13): 1, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36454558

RESUMO

Purpose: The purpose of this study was to identify a new candidate gene for keratoconus and congenital cataracts and further investigate its underlying pathogenic mechanisms. Methods: This study, using a Chinese family with keratoconus and congenital cataracts, 262 patients with sporadic keratoconus, and 20 patients with sporadic congenital cataract as subjects, used clinical and genetic analysis and in vitro cell experiments to detect genetic mutations and further investigate the underlying pathogenic mechanisms. Results: We found that a novel frameshift mutation of ERCC8 (NM_000082.3: c.394-398del, p. L132Nfs*6) is responsible for familial keratoconus with congenital cataracts. This mutation showed co-segregation with the phenotype in the family. This was revealed in another patient with sporadic keratoconus, absent in the 210 unrelated health controls, and considered to be "disease-causing." ERCC8 was expressed both in the cornea and lens. Through an in vitro cell experiment, we further demonstrated that the mutant proteins of ERCC8 were degraded and could lead to an insufficient dose of the ERCC8 protein. An insufficient dose reduced the DNA damage repair ability of human corneal fibroblast (HTK) and lens epithelial cells (HLEC) treated with hydrogen peroxide, leading to both cells showing higher DNA damage levels. In addition, it decreased cell viability, resulting in decreased collagen expression in HTK and increased apoptosis in HLEC via aberrant activation of the unfolded protein response. All these results suggested that ERCC8 plays an important role in the normal function of corneal stromal and lens epithelial cells. Conclusions: Our study showed that ERCC8 is a new gene associated with keratoconus and congenital cataracts.Chinese Abstract.


Assuntos
Catarata , Ceratocone , Cristalino , Humanos , Mutação da Fase de Leitura , Ceratocone/genética , Córnea , Catarata/genética , Fatores de Transcrição , Enzimas Reparadoras do DNA
13.
J Virus Erad ; 8(4): 100308, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36531082

RESUMO

Background: A community COVID-19 outbreak caused by the B.1.1.7 SARS-CoV-2 variant occurred in Taiwan in May 2021. High-risk populations such as people living with HIV (PLWH) were recommended to receive two doses of COVID-19 vaccines. While SARS-CoV-2 vaccines have demonstrated promising results in general population, real-world information on the serological responses remains limited among PLWH. Methods: PLWH receiving the first dose of SARS-CoV-2 vaccine from 2020 to 2021 were enrolled. Determinations of anti-SARS-CoV-2 spike IgG titers were performed every one to three months, the third dose of the SARS-CoV-2 vaccine or confirmed SARS-CoV-2 infection. All serum samples were tested for anti-nucleocapsid antibody and those tested positive were excluded from analysis. Results: A total of 1189 PLWH were enrolled: 829 (69.7%) receiving two doses of the AZD1222 vaccine, 232 (19.5%) of the mRNA-1273 vaccine, and 128 (10.8%) of the BNT162b2 vaccine. At all time-points, PLWH receiving two doses of mRNA vaccines had consistently higher antibody levels than those receiving the AZD1222 vaccine (p <0.001 for all time-point comparisons). Factors associated with failure to achieve an anti-spike IgG titer >141 BAU/mL within 12 weeks, included type 2 diabetes mellitus (DM) (adjusted odds ratio [aOR], 2.24; 95% CI, 1.25-4), a CD4 T cell count <200 cells/mm3 upon receipt of the first dose of vaccination (aOR, 3.43; 95% CI, 1.31-9) and two homologous AZD1222 vaccinations (aOR, 16.85; 95%CI, 10.13-28). For those receiving two doses of mRNA vaccines, factors associated with failure to achieve an anti-spike IgG titer >899 BAU/mL within 12 weeks were a CD4 T cell count <200 cells/mm3 on first-dose vaccination (aOR, 3.95; 95% CI, 1.08-14.42) and dual BNT162b2 vaccination (aOR, 4.21; 95% CI, 2.57-6.89). Conclusions: Two doses of homologous mRNA vaccination achieved significantly higher serological responses than vaccination with AZD1222 among PLWH. Those with CD4 T cell counts <200 cells/mm3 and DM had consistently lower serological responses.

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(6): 1637-1642, 2022 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-36476882

RESUMO

OBJECTIVE: To calculate the cut-off values of speed of platelet recovery and its R-squared in patients with acute myeloid leukemia (AML) after initial induction chemotherapy, which were used to predict the complete remission (CR) of the first induction chemotherapy, and guide the clinic to choose the next appropriate chemotherapy regimen as soon as possible. METHODS: A total of 117 patients with newly diagnosed AML in the Second Hospital of Shanxi Medical University were included. Patients were diagnosed by morphology, immunology, cytogenetics, and molecular biology (MICM) classification, and the risk stratification was evaluated in combination with the clinical situations of the patients at the time of admission. The peripheral platelet counts after the first induction chemotherapy were detected and the linear regression equation was used to calculate the recovery speed of platelet counts in 5 consecutive blood cell analysis before discharge. According to the ROC curve, the cut-off value between the recovery speed and the R-squared was calculated, and the cut-off value was used to divide the patients into different groups. The differences between groups were compared by Pearson χ2 test to observe the remission effect of the first induction chemotherapy. RESULTS: ROC curve analysis showed that the cut-off value for predicting the platelet recovery speed and its R-squared of the first induction chemotherapy to achieve remission was 4.059 5×109/(L·d) and 72.7%, the sensitivity was 77% and 63.9%, the specificity was 62.5% and 67.9%, and the Youden index was 0.395 and 0.318, respectively. The patients were divided into different groups and compared according to the above cut-off values, and the results showed statistical differences (P<0.001, P=0.001). CONCLUSION: The cut-off value of platelet recovery speed and its R-squared after the first induction chemotherapy calculated by peripheral platelet count and ROC curve in AML patients can be used as an index to evaluate the remission. The faster the platelet recovery speed after chemotherapy is, the more likely patients achieve remission. The more stable the platelet recovery tendency is, the more likely patients achieve remission too.


Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Humanos , Citogenética , Leucemia Mieloide Aguda/tratamento farmacológico , Biologia Molecular
15.
New Phytol ; 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36478218

RESUMO

Buckwheat is an important crop which originated in China and spread widely across Eurasia. However, exactly where in China domestication took place remains controversial. Archaeological and palynological records suggest a longer cultivation history of buckwheat in northern China than in southwestern China, but this conflicts with phylogenetic evidence implicating southwestern China as the centre of origin and diversity of buckwheat. We investigate alternative methodologies for inferring the occurrence of buckwheat cultivation and suggest that relative abundance could provide a reliable measure for distinguishing between wild and cultivated buckwheat in both present-day and fossil samples. Approximately 12 800-yr palaeoecological record shows that Fagopyrum pollen occurred only infrequently before the early Holocene. As southwestern China entered the early agricultural period, c. 8000-7000 yr ago, a slight increase in abundance of Fagopyrum pollen was observed. Approximately 4000 yr ago, concurrent with the Pu minority beginning to develop dry-land agriculture, the abundance of Fagopyrum pollen increased significantly, suggesting the cultivation of this crop. Fagopyrum pollen rose to a maximum value c. 1270 yr ago, suggesting an intensification of agricultural activity. These findings fill a gap in the Fagopyrum pollen record in southwestern China and provide new indications that early cultivation may have occurred in this region.

16.
NPJ Precis Oncol ; 6(1): 95, 2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36575215

RESUMO

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.

17.
Front Oncol ; 12: 1064127, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568190

RESUMO

Introduction: Glutamine is characterized as the nutrient required in tumor cells. The study based on glutamine metabolism aimed to develop a new predictive factor for pan-cancer prognostic and therapeutic analyses and to explore the mechanisms underlying the development of cancer. Methods: The RNA-sequence data retrieved from TCGA, ICGC, GEO, and CGGA databases were applied to train and further validate our signature. Single-cell RNA transcriptome data from GEO were used to investigate the correlation between glutamine metabolism and cell cycle progression. A series of bioinformatics and machine learning approaches were applied to accomplish the statistical analyses in this study. Results: As an individual risk factor, our signature could predict the overall survival (OS) and immunotherapy responses of patients in the pan-cancer analysis. The nomogram model combined several clinicopathological features, provided the GMscore, a readable measurement to clinically predict the probability of OS and improve the predictive capacity of GMscore. While analyzing the correlations between glutamine metabolism and malignant features of the tumor, we observed that the accumulation of TP53 inactivation might underlie glutamine metabolism with cell cycle progression in cancer. Supposedly, CAD and its upstream genes in glutamine metabolism would be potential targets in the therapy of patients with IDH-mutated glioma. Immune infiltration and sensitivity to anti-cancer drugs have been confirmed in the high-risk group. Discussion: In summary, glutamine metabolism is significant to the clinical outcomes of patients with pan-cancer and is tightly associated with several hallmarks of a malignant tumor.

18.
J Chem Phys ; 157(17): 174106, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36347690

RESUMO

Machine learning techniques have received growing attention as an alternative strategy for developing general-purpose density functional approximations, augmenting the historically successful approach of human-designed functionals derived to obey mathematical constraints known for the exact exchange-correlation functional. More recently, efforts have been made to reconcile the two techniques, integrating machine learning and exact-constraint satisfaction. We continue this integrated approach, designing a deep neural network that exploits the exact constraint and appropriate norm philosophy to de-orbitalize the strongly constrained and appropriately normed (SCAN) functional. The deep neural network is trained to replicate the SCAN functional from only electron density and local derivative information, avoiding the use of the orbital-dependent kinetic energy density. The performance and transferability of the machine-learned functional are demonstrated for molecular and periodic systems.

19.
ACS Appl Bio Mater ; 5(11): 5377-5385, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36343279

RESUMO

Regulation of protein activity is important in their applications for biomedicine and therapeutics. Here, an approach for the regulation of protein bioactivity through molecular confinement provided by oligoethylene glycol (OEG)-based dendronized chitosan (DCS) hydrogels is reported. Structural effects on their thermoresponsiveness are investigated. The highly transparent hydrogels are formed from thermoresponsive DCSs through their thermal dehydration and exhibit an intriguing reversible sol-gel transition property when triggered at physiological temperatures. The thermo-gelling behavior and mechanical strength of these hydrogels are investigated, and possible effects from hydrophobicity of the OEG dendrons, grafting rates of the dendrons on the chitosan main chain, and solid content of polymers are examined. These DCS hydrogels are found to have lamellar morphologies and can provide characteristic hydrophobicity microenvironments formed through the crowded OEG dendrons, which show a higher level of confinement to guest proteins. This allows the DCS hydrogels remarkable activity protection capability to proteins. Furthermore, these DCS hydrogels inherit the degradability from chitosan, allowing protein release from these hydrogels through the controllable ways without impairing their activities.


Assuntos
Quitosana , Dendrímeros , Quitosana/farmacologia , Coloides , Hidrogéis , Polímeros
20.
Thromb J ; 20(1): 69, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414932

RESUMO

BACKGROUND: It is well established that lipoprotein(a)[Lp(a)] play a vital role in atherosclerosis. Whether Lp(a) can predict recurrence of cardiovascular events (CVEs) in prior CVEs patients is still unclear. We aim to investigate its association with subsequent long-term adverse events in this high-risk population. METHODS: A total of 4,469 patients with prior CVEs history after PCI were consecutively enrolled and categorized according Lp(a) values of < 10 (low), 10 to 30 (medium), and ≥ 30 mg/dL (high). The primary endpoint was MACCE, a composite of all-cause death, myocardial infarction, stroke and unplanned revascularization. RESULTS: During an average of 5.0 years of follow-up, 1,078 (24.1%) and 206 (4.6%) patients experienced MACCE and all-cause death with 134 (3.0%) of whom from cardiac death. The incidence of MACCE, all-cause death and cardiac death were significantly higher in the high Lp(a) group (p < 0.05). After adjustment of confounding factors, high Lp(a) level remained an independent risk factor for MACCE (adjusted HR 1.240, 95%CI 1.065-1.443, p = 0.006), all-cause death (adjusted HR 1.445, 95%CI 1.023-2.042, p = 0.037) and cardiac death (adjusted HR 1.724, 95%CI 1.108-2.681, p = 0.016). This correlation remained significant when treated as a natural logarithm-transformed continuous variable. This finding is relatively consistent across subgroups and confirmed again in two sensitivity analyses. CONCLUSIONS: Our present study confirmed that Lp(a) was an independent predictor for recurrent CVEs in patients with established CVEs, illustrating that Lp(a) level might be a valuable biomarker for risk stratification and prognostic assessment in this high-risk population.

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