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1.
Turk J Gastroenterol ; 33(1): 44-52, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35040787

RESUMO

BACKGROUND: Many studies and meta-analyses have investigated the associations among proton pump inhibitors (PPIs), spontaneous bacterial peritonitis (SBP), portosystemic encephalopathy (PSE), and other infections. However, these studies had limitations, including the omission of several relevant studies and drawing conclusions, based on the abstracts without consulting the full-text of the articles. To evaluate the association between PPIs and complications arising from cirrhosis and risks of PPI use in patients with cirrhosis. METHODS: Data were extracted from the EMBASE, PubMed, Cochrane, and Google Scholar databases. The Newcastle-Ottawa scale was used to assess the quality of the selected studies. RESULTS: A total of 29 studies (13 case-control and 16 cohort studies) involving 20,484 patients were included in the meta-analysis. The total relative risk (RR) for the 23 studies which investigated SBP was 1.31, and the 95% CI was 1.10-1.55 (I2 = 73.0%). The total RR for the 7 studies which examined PSE was 1.25 (95% CI 0.85-1.84, I2 = 96.1%). For the 7 studies which analyzed overall infection, the total RR was 1.37 (95% CI 1.07-1.76, I2 = 79.3%). The RR for the 2 cohort studies that assessed mortality was 1.39 (95% CI 0.85-2.27, I2 = 0.0%). CONCLUSION: PPI use in cirrhosis patients increased the SBP and overall infection risk. PPIs should be considered with appropriate indications when the benefits exceed the risks in cirrhosis patients with ascites.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35041400

RESUMO

The synergistic effect of Na+/Al3+ dual doping is investigated to improve the structural stability and electrochemical performance of LiNi0.88Co0.08Mn0.04O2 cathodes for Li-ion batteries. Rietveld refinement and density functional theory calculations confirm that Na+/Al3+ dual doping changes the lattice parameters of LiNi0.88Co0.08Mn0.04O2. The changes in the lattice parameters and degree of cation mixing can be alleviated by maintaining the thickness of the LiO6 slab because the energy of Al-O bonds is higher than that of transition metal (TM)-O bonds. Moreover, Na is an abundant and inexpensive metal, and unlike Al3+, Na+ can be doped into the Li slab. The ionic radius of Na+ (1.02 Å) is larger than that of Li+ (0.76 Å); therefore, when Na+ is inserted into Li sites, the Li slab expands, indicating that Na+ serves as a pillar ion for the Li diffusion pathway. Upon dual doping of the Li and TM sites of Ni-rich Ni0.88Co0.08Mn0.04O2 (NCM) with Na+ and Al3+, respectively, the lattice structure of the obtained NNCMA is more ideal than those of bare NCM and Li+- and Na+-doped NCM (NNCM and NCMA, respectively). This suggests that NNCMA with an ideal lattice structure presents several advantages, namely, excellent structural stability, a low degree of cation mixing, and favorable Li-ion diffusion. Consequently, the rate capability of NNCMA (83.67%, 3 C/0.2 C), which presents favorable Li-ion diffusion because of the expanded Li sites, is higher than those of bare NCM (78.68%), NNCM (81.15%), and NCMA (83.18%). The Rietveld refinement, differential capacity analysis, and galvanostatic intermittent titration technique results indicate that NNCMA exhibits low polarization, favorable Li-ion diffusion, and a low degree of cation mixing; moreover, its phase transition is hindered. Consequently, NNCMA demonstrates a higher capacity retention (84%) than bare NCM (79%), NNCM (82%), and NCMA (82%) after 50 cycles at 1 C. This study provides insight into the fabrication of Ni-rich NCMs with excellent electrochemical performance.

3.
Hum Mol Genet ; 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35043955

RESUMO

Human leukocyte antigen (HLA) gene variants in the major histocompatibility complex (MHC) region are associated with numerous complex human diseases and quantitative traits. Previous phenome-wide association studies (PheWAS) for this region demonstrated that HLA association patterns to the phenome have both population-specific and population-shared components. We performed MHC PheWAS in the Korean population by analyzing associations between phenotypes and genetic variants in the MHC region using the Korea Biobank Array project data samples from the Korean Genome and Epidemiology Study (KoGES) cohorts. Using this single-population dataset, we curated and analyzed 82 phenotypes for 125 673 Korean individuals after imputing HLA using CookHLA, a recently developed imputation framework. More than one-third of these phenotypes showed significant associations, confirming 56 known associations and discovering 13 novel association signals that were not reported previously. In addition, we analyzed heritability explained by the variants in the MHC region and genetic correlations among phenotypes based on the MHC variants.

4.
J Clin Immunol ; 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34973142

RESUMO

PURPOSE: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. METHODS: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN's Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. RESULTS: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12-7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06-64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin [Formula: see text] ng/mL, OR: 2.16, 95% CI: 1.28-3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 - 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12-2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10-2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21-14.5, p = 0.019). CONCLUSION: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

5.
Neuromodulation ; 25(1): 53-63, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35041588

RESUMO

OBJECTIVE: The objective of this preclinical study was to examine the responses of the brain to noxious stimulation in the presence and absence of different modes of spinal cord stimulation (SCS) using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI). MATERIALS AND METHODS: Sprague-Dawley rats were randomized to groups based on the mode of SCS delivered which included tonic stimulation (n = 27), burst stimulation (n = 30), and burst-cycle stimulation (n = 29). The control (sham) group (n = 28) received no SCS. The SCS electrode was inserted between T10 and T12 spinal levels prior to fMRI session. The experimental protocol for fMRI acquisition consisted of an initial noxious stimulation phase, a treatment phase wherein the SCS was turned on concurrently with noxious stimulation, and a residual effect phase wherein the noxious stimulation alone was turned on. The responses were statistically analyzed through paired t-test and the results were presented as z-scores for the quantitative analysis of the fMRI data. RESULTS: The treatment with different SCS modes attenuated the BOLD brain responses to noxious hindlimb stimulation. The tonic, burst, and burst-cycle SCS treatment attenuated BOLD responses in the caudate putamen (CPu), insula (In), and secondary somatosensory cortex (S2). There was little to no corresponding change in sham control in these three regions. The burst and burst-cycle SCS demonstrated greater attenuation of BOLD signals in CPu, In, and S2 compared to tonic stimulation. CONCLUSION: The high-resolution fMRI study using a rat model demonstrated the potential of different SCS modes to act on several pain-matrix-related regions of the brain in response to noxious stimulation. The burst and burst-cycle SCS exhibited greater brain activity reduction in response to noxious hindlimb stimulation in the caudate putamen, insula, and secondary somatosensory cortex compared to tonic stimulation.


Assuntos
Neuralgia , Estimulação da Medula Espinal , Animais , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Medula Espinal/diagnóstico por imagem
6.
Alzheimers Res Ther ; 14(1): 6, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996525

RESUMO

BACKGROUND: Neurofilament light chain (NFL) level has been suggested as a blood-based biomarker for neurodegeneration in dementia. However, the association between baseline NFL levels and cognitive stage transition or cortical thickness is unclear. This study aimed to investigate whether baseline NFL levels are associated with cognitive stage transition or cortical thickness in mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants. METHODS: This study analyzed data on participants from the independent validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE-V) study. Among the participants of KBASE-V study, 53 MCI and 146 CU participants who were followed up for ≥ 2 years and had data on the serum NFL levels were eligible for inclusion in this study. Participants were classified into three groups according to baseline serum NFL levels of low, middle, or high. RESULTS: The Kaplan-Meier analysis showed association between the serum NFL tertiles and risk of cognitive stage transition in MCI (P = 0.002) and CU (P = 0.028) participants, analyzed separately. The same is true upon analysis of MCI and CU participants together (P < 0.001). In MCI participants, the highest serum NFL tertile and amyloid-beta positivity were independent predictors for cognitive stage transition after adjusting for covariates. For CU participants, only amyloid-beta positivity was identified to be an independent predictor. CONCLUSION: The study shows that higher serum NFL tertile levels correlate with increased risk of cognitive stage transition in both MCI and CU participants. Serum NFL levels were negatively correlated with the mean cortical thickness of the whole-brain and specific brain regions.

8.
Chem Commun (Camb) ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34981101

RESUMO

We herein describe an ultrasensitive RNase H assay by utilizing CRISPR/Cas12a collateral cleavage activity. Based on this unique design principle, the RNase H activity was successfully determined down to 0.00024 U mL-1, which is quite superior to those of alternative approaches.

9.
Acta Crystallogr D Struct Biol ; 78(Pt 1): 59-68, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34981762

RESUMO

CRISPR-Cas systems are well known host defense mechanisms that are conserved in bacteria and archaea. To counteract CRISPR-Cas systems, phages and viruses have evolved to possess multiple anti-CRISPR (Acr) proteins that can inhibit the host CRISPR-Cas system via different strategies. The expression of acr genes is controlled by anti-CRISPR-associated (Aca) proteins that bind to an upstream promoter and regulate the expression of acr genes during transcription. Although the role of Aca as a transcriptional repressor has been demonstrated, the mechanism of action of Aca has not been determined. Here, the molecular mechanism underlying the Aca2-mediated transcriptional control of acr genes was elucidated by determining the crystal structure of Aca2 from Oceanimonas smirnovii at a high resolution of 1.92 Å. Aca2 forms a dimer in solution, and dimerization of Aca2 is critical for specific promoter binding. The promoter-binding strategy of dimeric Aca2 was also revealed by performing mutagenesis studies. The atomic structure of the Aca family shown in this study provides insights into the fine regulation of host defense and immune-escape mechanisms and also demonstrates the conserved working mechanism of the Aca family.

10.
PLoS One ; 17(1): e0259638, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35030160

RESUMO

BACKGROUND: Sudden cardiac death (SCD) and stroke-related events accompanied by atrial fibrillation (AF) can affect morbidity and mortality in hypertrophic cardiomyopathy (HCM). This study sought to evaluate a scoring system predicting cardio-cerebral events in HCM patients using cardiopulmonary exercise testing (CPET). METHODS: We investigated the role of a previous prediction model based on CPET, the HYPertrophic Exercise-derived Risk score for Heart Failure-related events (HyperHF), which is derived from peak circulatory power ventilatory efficiency and left atrial diameter (LAD), for predicting a composite of SCD-related (SCD, serious ventricular arrhythmia, death from cardiac cause, heart failure admission) and stroke-related (new-onset AF, acute stroke) events. The Novel HyperHF risk model using left atrial volume index (LAVI) instead of LAD was proposed and compared with the previous HCM Risk-SCD model. RESULTS: A total of 295 consecutive HCM patients (age 59.9±13.2, 71.2% male) who underwent CPET was included in the present study. During a median follow-up of 742 days (interquartile range 384-1047 days), 29 patients (9.8%) experienced an event (SCD-related event: 14 patients (4.7%); stroke-related event: 17 patients (5.8%)). The previous model for SCD risk score showed fair prediction ability (AUC of HCM Risk-SCD 0.670, p = 0.002; AUC of HyperHF 0.691, p = 0.001). However, the prediction power of Novel HyperHF showed the highest value among the models (AUC of Novel HyperHF 0.717, p<0.001). CONCLUSIONS: Both conventional HCM Risk-SCD score and CPET-derived HyperHF score were useful for prediction of overall risk of SCD-related and stroke-related events in HCM. Novel HyperHF score using LAVI could be utilized for a better prediction power.

11.
J Korean Med Sci ; 37(3): e10, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35040294

RESUMO

BACKGROUND: Injury is a social problem that causes health and property losses, and it is important to identify the size and trend of injury for efficient prevention and management. Therefore, this study analyzed the trends in injury mortality and hospitalization rates from 2005 to 2019 in Korea. METHODS: Using mortality data by Statistics Korea and Korea National Hospital Discharge In-depth injury survey by the Korea Disease Control and Prevention Agency (KDCA), age standardized rates were calculated for death and hospitalization to analyze trends and annual changes with the joinpoint regression model. In addition, annual changes in the hospitalization rate of the transport accident and fall injuries by age group were analyzed, which are the major causes of injuries. RESULTS: From 2005 to 2019, the injury mortality rate has been on the decline, but the injury hospitalization rate has been on the rise. The annual rate of change varied depending on the injury mechanism, but the mortality rate tended to decrease or remain similar level, while the rate of hospitalization has steadily increased. In addition, by age group, injury mortality and hospitalization rates were high in the elderly. In particular, the hospitalization rate of the elderly was higher when comparing the hospitalization rate of the children in transport accidents and falls. Pedestrian transport accidents tended to decrease under the age of 15, but remained similar for those aged 65 and older, and bicycle accidents tended to increase in both groups. In addition, hospitalization rates were higher in the fall, with both groups showing a statistically significant increase in hospitalization rates caused by falls. CONCLUSION: This study analyzed the trend of injury mortality and hospitalization and found that transport accidents and falls may vary depending on the means or age of the accident. Since injury is a big social problem that is a burden of disease, safety education and legal sanctions for injury prevention should be further improved in the future, especially by prioritizing vulnerable groups by age and detailed mechanisms of injury.

12.
J Korean Med Sci ; 37(3): e22, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35040297

RESUMO

BACKGROUND: To evaluate the health status of healthcare workers (doctors and nurses) compared to those in the general population based on the National Health Insurance Service database and the cause of death data from Statistics Korea. METHODS: The subjects of this study were 104,484 doctors and 220,310 nurses working in healthcare facilities from 2002 to 2017, and who had undergone at least one general medical examination. Based on the subject definition, the subject data were extracted from the National Health Insurance healthcare facility database and qualification database. We collected medical use details included in the research database, general medical examination results, medical history included in the health examination database, and additional data on the cause of death from the National Statistics database to analyze the main cause of death and mortality. RESULTS: In terms of the major causes of death and mortality among healthcare workers, the mortality rate associated with intentional self-harm, injury, transportation accident, heart disease, addiction, and falling was significantly higher than that in the general population. Further, the prevalence of respiratory and gastrointestinal diseases was high. When analyzing the proportional mortality ratio (PMR) by cause of death for healthcare workers, the PMR values for death related to malignant neoplasm was the highest. In terms of diseases, both doctors and nurses had higher rates of infectious diseases such as maternal sepsis, rubella, and measles. CONCLUSION: The health status of healthcare workers differs from that of the general population. Thus, it is important to consider the occupational characteristics of healthcare personnel. This study is unique in that it was conducted based on medical use indicators rather than survey data.

13.
Transplant Cell Ther ; 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35021131

RESUMO

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplant cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Here, we compared the outcomes in children and adolescents with high-risk acute leukemia after HRD HSCT with PTCy (n=35) and MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years, respectively. No engraftment failure was observed in both groups. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), moderate to severe chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different between the two groups. The 3-year severe chronic GVHD-free/relapse-free (GRFS), leukemia-free (LFS) and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence intervals [CI], 45.8%, 80.0%) versus 49.8% (95% CI, 34.9%, 64.7%; p=0.318), 74.4% (95% CI, 58.7%, 90.1%) versus 67.5% (95% CI, 53.4%, 81.6%; p=0.585), and 88.6% (95% CI, 78.0%, 99.2%) versus 83.7% (95% CI, 72.5%, 94.9%; p=0.968), respectively. In a subgroup analysis of acute lymphoblastic leukemia patients (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates of the HRD and MUD groups were 49.4% (95% CI, 24.3%, 74.5%) versus 39.5% (95% CI, 19.7%, 59.3%; p=0.601), 61.8% (95% CI, 37.5%, 86.1%) versus 63.6% (95% CI, 44.4%, 82.8%; p=0.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1%, 98.3%; p=0.445), respectively. In acute myeloid leukemia patients (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates of the HRD and MUD groups were 80.8% (95% CI, 61.2%, 100%) versus 61.9% (95% CI, 37.8%, 86.0%; p=0.326), 87.1% (95% CI, 70.2%, 100%) versus 73.9% (95% CI, 51.8%, 96.0%; p=0.478), and 93.8% (95% CI, 81.8%, 100%) versus 85.6% (95% CI, 67.0%, 100%; p=0.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

14.
World J Mens Health ; 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35021297

RESUMO

Antisperm antibodies (ASA), as a cause of male infertility, have been detected in infertile males as early as 1954. Multiple causes of ASA production have been identified, and they are due to an abnormal exposure of mature germ cells to the immune system. ASA testing (with mixed anti-globulin reaction, and immunobead binding test) was described in the WHO manual 5th edition and is most recently listed among the extended semen tests in the WHO manual 6th edition. The relationship between ASA and infertility is somewhat complex. The presence of sperm agglutination, while insufficient to diagnose immunological infertility, may indicate the presence of ASA. However, ASA can also be present in the absence of any sperm agglutination. The andrological management of ASA depends on the etiology and individual practices of clinicians. In this article, we provide a comprehensive review of the causes of ASA production, its role in immunological male infertility, clinical indications of ASA testing, and the available therapeutic options. We also provide the details of laboratory procedures for assessment of ASA together with important measures for quality control. Additionally, laboratory and clinical scenarios are presented to guide the reader in the management of ASA and immunological male infertility. Furthermore, we report the results of a recent worldwide survey, conducted to gather information about clinical practices in the management of immunological male infertility.

15.
World J Mens Health ; 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35021311

RESUMO

PURPOSE: The success of vasectomy is determined by the outcome of a post-vasectomy semen analysis (PVSA). This article describes a step-by-step procedure to perform PVSA accurately, report data from patients who underwent post vasectomy semen analysis between 2015 and 2021 experience, along with results from an international online survey on clinical practice. MATERIALS AND METHODS: We present a detailed step-by-step protocol for performing and interpretating PVSA testing, along with recommendations for proficiency testing, competency assessment for performing PVSA, and clinical and laboratory scenarios. Moreover, we conducted an analysis of 1,114 PVSA performed at the Cleveland Clinic's Andrology Laboratory and an online survey to understand clinician responses to the PVSA results in various countries. RESULTS: Results from our clinical experience showed that 92.1% of patients passed PVSA, with 7.9% being further tested. A total of 78 experts from 19 countries participated in the survey, and the majority reported to use time from vasectomy rather than the number of ejaculations as criterion to request PVSA. A high percentage of responders reported permitting unprotected intercourse only if PVSA samples show azoospermia while, in the presence of few non-motile sperm, the majority of responders suggested using alternative contraception, followed by another PVSA. In the presence of motile sperm, the majority of participants asked for further PVSA testing. Repeat vasectomy was mainly recommended if motile sperm were observed after multiple PVSA's. A large percentage reported to recommend a second PVSA due to the possibility of legal actions. CONCLUSIONS: Our results highlighted varying clinical practices around the globe, with controversy over the significance of non-motile sperm in the PVSA sample. Our data suggest that less stringent AUA guidelines would help improve test compliance. A large longitudinal multi-center study would clarify various doubts related to timing and interpretation of PVSA and would also help us to understand, and perhaps predict, recanalization and the potential for future failure of a vasectomy.

16.
Theranostics ; 12(1): 105-125, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34987637

RESUMO

Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.

17.
Artigo em Inglês | MEDLINE | ID: mdl-35032694

RESUMO

BACKGROUND: Hereditary-alpha tryptasemia (HαT) is the most common etiology for elevated basal serum tryptase (BST). However, the utility of tryptase genotyping of individuals with elevated BST in general clinical practice remains undefined. Moreover, studies showing associations between elevated BST and chronic kidney disease (CKD), myelodysplastic syndrome (MDS), rheumatoid arthritis (RA), or eosinophilic esophagitis (EoE) did not include tryptase genotyping. OBJECTIVE: To determine the utility of tryptase genotyping among individuals with moderate elevations in BST at a regional health system. METHODS: Clinical and laboratory data from 109 subjects with basal tryptase values ≥ 7.5 ng/mL who were tested for HαT or had a disorder previously linked to elevated BST were collected retrospectively by chart review. RESULTS: 58 subjects had elevated BST defined as ≥11.5 ng/mL. 63.8% (n=37/58) had HαT, 12.1% (n=7/58) had CKD, and 20.7% (n=12/58) had clonal myeloid disorders. 6.9% (n=4/58) of subjects with elevated BST had negative testing for HαT, CKD, and myeloid neoplasms. 2 subjects with CKD, 1 subject with MDS, and 1 with myeloid hypereosinophilic syndrome (HES) had negative testing for HαT. Among subjects with elevated BST and more than one tryptase measurement, 41.5% (n=22/53) had BST variability that exceeded the 20% plus 2 formula. Increased BST variability was found in subjects with HαT, all forms of mastocytosis, CKD, MDS, and those with no associated diagnosis. CONCLUSIONS: HαT, CKD, and clonal myeloid disorders or a combination of the three constitute approximately 90% of individuals with elevated BST in clinical practice. Myeloid neoplasms were over-represented in this cohort relative to population prevalence data suggesting tryptase measurement selection bias by clinicians or higher prevalence. Elevated BST is associated with increased tryptase variability, regardless of etiology.

18.
PLoS One ; 17(1): e0261448, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35061730

RESUMO

Despite the importance of Helicobacter pylori infection and portal hypertension (PH)-associated gastrointestinal (GI) diseases, such as esophageal varices and portal hypertensive gastropathy (PHG), the impact of H. pylori infection on PH-related GI complications has not yet been elucidated. This meta-analysis investigated the association between H. pylori infection and the risk of PH-related GI complications. An electronic search for original articles published before May 2020 was performed using PubMed, EMBASE, and the Cochrane Library. Independent reviewers conducted the article screening and data extraction. We used the generic inverse variance method for the meta-analysis, and Begg's rank correlation test and Egger's regression test to assess publication bias. A total of 1,148 cases of H. pylori infection and 1,231 uninfected controls were included from 13 studies. H. pylori infection had no significant association with esophageal varices [relative risk (RR) = 0.96, 95% confidence interval (CI) = 0.87-1.06 for all selected studies; RR = 0.95, 95% CI = 0.84-1.07 for cohort studies; odds ratio (OR) = 0.96, 95% CI = 0.60-1.54 for case-control studies]. Although H. pylori infection was significantly associated with PHG in case-control studies [OR = 1.86, 95% CI = 1.17-2.96], no significant differences were found in the cohort studies [RR = 0.98, 95% CI = 0.91-1.05] or all studies combined [RR = 1.18, 95% CI = 0.93-1.52]. In conclusion, H. pylori infection was not associated with the risk of PH-related GI complications. Clinicians should carefully treat cirrhotic patients with PH-related GI complications, regardless of H. pylori infection.

19.
Anesthesiology ; 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35051263

RESUMO

BACKGROUND: The antitumor effects of natural killer cells, helper T cells, and cytotoxic T cells after cancer surgery were reported previously. This study hypothesized that propofol-based anesthesia would have fewer harmful effects on immune cells than volatile anesthetics-based anesthesia during colorectal cancer surgery. METHODS: In total, 153 patients undergoing colorectal cancer surgery were randomized and included in the analysis. The primary outcome was the fraction of circulating natural killer cells over time in the propofol and sevoflurane groups. The fractions of circulating natural killer, type 1, type 17 helper T cells, and cytotoxic T cells were investigated. The fractions of CD39 and CD73 expressions on circulating regulatory T cells were investigated, along with the proportions of circulating neutrophils, lymphocytes, and monocytes. RESULTS: The fraction of circulating natural killer cells was not significantly different between the propofol and sevoflurane groups until 24 h postoperatively (20.4 ± 13.4% vs. 20.8 ± 11.3%, 17.9 ± 12.7% vs. 20.7 ± 11.9%, and 18.6 ± 11.6% vs. 21.3 ± 10.8% before anesthesia and after 1 and 24 h after anesthesia, respectively; difference [95% CI], -0.3 [-4.3 to 3.6], -2.8 [-6.8 to 1.1], and -2.6 [-6.2 to 1.0]; P = 0.863, P = 0.136, and P = 0.151 before anesthesia and after 1 and 24 h, respectively). The fractions of circulating type 1 and type 17 helper T cells, cytotoxic T cells, and CD39+ and CD73+ circulating regulatory T cells were not significantly different between the two groups. The neutrophil to lymphocyte ratio in both groups remained within the normal range and was not different between the groups. CONCLUSIONS: Propofol-based anesthesia was not superior to sevoflurane-based anesthesia in terms of alleviating suppression of immune cells including natural killer cells and T lymphocytes during colorectal cancer surgery.

20.
BMC Plant Biol ; 22(1): 4, 2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979940

RESUMO

BACKGROUND: Cynanchum wilfordii (Cw) and Cynanchum auriculatum (Ca) have long been used in traditional medicine and as functional food in Korea and China, respectively. They have diverse medicinal functions, and many studies have been conducted, including pharmaceutical efficiency and metabolites. Especially, Cw is regarded as the most famous medicinal herb in Korea due to its menopausal symptoms relieving effect. Despite the high demand for Cw in the market, both species are cultivated using wild resources with rare genomic information. RESULTS: We collected 160 Cw germplasm from local areas of Korea and analyzed their morphological diversity. Five Cw and one Ca of them, which were morphologically diverse, were sequenced, and nuclear ribosomal DNA (nrDNA) and complete plastid genome (plastome) sequences were assembled and annotated. We investigated the genomic characteristics of Cw as well as the genetic diversity of plastomes and nrDNA of Cw and Ca. The Cw haploid nuclear genome was approximately 178 Mbp. Karyotyping revealed the juxtaposition of 45S and 5S nrDNA on one of 11 chromosomes. Plastome sequences revealed 1226 interspecies polymorphisms and 11 Cw intraspecies polymorphisms. The 160 Cw accessions were grouped into 21 haplotypes based on seven plastome markers and into 108 haplotypes based on seven nuclear markers. Nuclear genotypes did not coincide with plastome haplotypes that reflect the frequent natural outcrossing events. CONCLUSIONS: Cw germplasm had a huge morphological diversity, and their wide range of genetic diversity was revealed through the investigation with 14 molecular markers. The morphological and genomic diversity, chromosome structure, and genome size provide fundamental genomic information for breeding of undomesticated Cw plants.


Assuntos
Cynanchum/genética , Variação Genética , Genoma de Planta , República da Coreia
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