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1.
Medicine (Baltimore) ; 100(35): e27125, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477155

RESUMO

ABSTRACT: We aimed to investigate the genetic and demographic differences and interactions between areas where observed genomic variations in Mycobacterium tuberculosis (M. tb) were distributed uniformly in cold and hot spots.The cold and hot spot areas were identified using the reported incidence of TB over the previous 5 years. Whole genome sequencing was performed on 291 M. tb isolates between January and June 2018. Analysis of molecular variance and a multifactor dimensionality reduction (MDR) model was applied to test gene-gene-environment interactions. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were computed to test the extent to which genetic mutation affects the TB epidemic using a multivariate logistic regression model.The percentage of the Beijing family strain in hot spots was significantly higher than that in cold spots (64.63% vs 50.69%, P = .022), among the elderly, people with a low BMI, and those having a history of contact with a TB patient (all P < .05). Individuals from cold spot areas had a higher frequency of out-of-town traveling (P < .05). The mutation of Rv1186c, Rv3900c, Rv1508c, Rv0210, and an Intergenic Region (SNP site: 3847237) showed a significant difference between cold and hot spots. (P < .001). The MDR model displayed a clear negative interaction effect of age groups with BMI (interaction entropy: -3.55%) and mutation of Rv0210 (interaction entropy: -2.39%). Through the mutations of Rv0210 and BMI had a low independent effect (interaction entropy: -1.46%).Our data suggests a statistically significant role of age, BMI and the polymorphisms of Rv0210 genes in the transmission and development of M. tb. The results provide clues for the study of susceptibility genes of M. tb in different populations. The characteristic strains showed a local epidemic. Strengthening genotype monitoring of strains in various regions can be used as an early warning signal of epidemic spillover.


Assuntos
Interações Hospedeiro-Patógeno/genética , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Adulto , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/epidemiologia
2.
BMC Infect Dis ; 21(1): 840, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412585

RESUMO

BACKGROUND: Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). China is the third in top 8 high TB burden countries and Guangxi is one of the high incidence areas in South China. Determine bacterial factors that affected TB incidence rate is a step toward Ending the TB epidemic. RESULTS: Genomes of M. tuberculosis cultures from a relatively high and low incidence region in Guangxi have been sequenced. 347 of 358(96.9%) were identified as M. tuberculosis. All the strains belong to Lineage 2 and Lineage 4, except for one in Lineage 1. We found that the genetic structure of the M. tuberculosis population in each county varies enormously. Low incidence rate regions have a lower prevalence of Beijing genotypes than other regions. Four isolates which harbored mutT4-48 also had mutT2-58 mutations. It is suggested that strains from the ancestors of modern Beijing lineage is circulating in Guangxi. Strains of modern Beijing lineage (OR=2.04) were more likely to acquire drug resistances than Lineage 4. Most of the lineage differentiation SNPs are related to cell wall biosynthetic pathways. CONCLUSIONS: These results provided a higher resolution to better understand the history of transmission of M. tuberculosis from/to South China. And the incidence rate of tuberculosis might be affected by bacterial population structure shaped by demographic history. Our findings also support the hypothesis that Modern Beijing lineage originated in South China.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/uso terapêutico , China/epidemiologia , Genótipo , Humanos , Incidência , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
3.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209006

RESUMO

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.


Assuntos
Condrócitos/citologia , Equol/farmacologia , Nitroprussiato/efeitos adversos , Osteoartrite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Modelos Biológicos , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
4.
J Biol Chem ; 297(2): 100980, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34302811

RESUMO

ß-Lactamase inhibitory protein (BLIP) consists of a tandem repeat of αß domains conjugated by an interdomain loop and can effectively bind and inactivate class A ß-lactamases, which are responsible for resistance of bacteria to ß-lactam antibiotics. The varied ability of BLIP to bind different ß-lactamases and the structural determinants for significant enhancement of BLIP variants with a point mutation are poorly understood. Here, we investigated the conformational dynamics of BLIP upon binding to three clinically prevalent class A ß-lactamases (TEM1, SHV1, and PC1) with dissociation constants between subnanomolar and micromolar. Hydrogen deuterium exchange mass spectrometry revealed that the flexibility of the interdomain region was significantly suppressed upon strong binding to TEM1, but was not significantly changed upon weak binding to SHV1 or PC1. E73M and K74G mutations in the interdomain region improved binding affinity toward SHV1 and PC1, respectively, showing significantly increased flexibility of the interdomain region compared to the wild-type and favorable conformational changes upon binding. In contrast, more rigidity of the interfacial loop 135-145 was observed in these BLIP mutants in both free and bound states. Consistently, molecular dynamics simulations of BLIP exhibited drastic changes in the flexibility of the loop 135-145 in all complexes. Our results indicated for the first time that higher flexibility of the interdomain linker, as well as more rigidity of the interfacial loop 135-145, could be desirable determinants for enhancing inhibition of BLIP to class A ß-lactamases. Together, these findings provide unique insights into the design of enhanced inhibitors.

5.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069880

RESUMO

This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). The supernatant was separated from the SB hydrolysate and freeze-dried. As the hydrolysis time extended to 6 h, soluble protein content increased from 187.1 to 565.8 mg/g, and peptide content increased from 112.8 to 421.9 mg/g, while inhibition of CMF increased from 75.0% to 88.4%. Decreasing the CMF inhibitory activity from 88.4% to 42.1% by simulated gastrointestinal digestion (FHHP-PN6 was further hydrolyzed by gastrointestinal enzymes, F-HHP-PN6-PP) reduced the CMF inhibitory activity of F-HHP-PN6. Using gel filtration chromatography, the F-HHP-PN6-PP was fractioned into six fractions. The molecular weight of the fifth fraction from F-HHP-PN6-PP was between 340 and 290 Da, and the highest inhibitory efficiency ratio (IER) on CMF was 238.9%/mg/mL. Further purification and identification of new peptides with CMF inhibitory activity presented the peptide sequences in Ser-Ala-Gln, Pro-Trp, and Val-Gly-Gly-Thr; the IERs were 361.7, 3230.0, and 302.9%/mg/mL, respectively.


Assuntos
Bass/metabolismo , Colesterol/química , Hidrolisados de Proteína/farmacologia , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Antioxidantes/farmacologia , Fermentação , Hidrólise , Pressão Hidrostática , Micelas , Peso Molecular , Oligopeptídeos , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Hidrolisados de Proteína/metabolismo , Proteínas/química , Proteínas/metabolismo , Proteólise
6.
J Virol ; 95(17): e0081621, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34133900

RESUMO

The complete eradication of human immunodeficiency virus type 1 (HIV-1) is blocked by latent reservoirs in CD4+ T cells and myeloid lineage cells. Toll-like receptors (TLRs) can induce the reversal of HIV-1 latency and trigger the innate immune response. To the best of our knowledge, there is little evidence showing the "killing" effect of TLR1/2 agonists but only a small "shock" potential. To identify a new approach for eradicating the HIV latent reservoir, we evaluated the effectiveness of SMU-Z1, a novel small-molecule TLR1/2 agonist, in the "shock-and-kill" strategy. The results showed that SMU-Z1 could enhance latent HIV-1 transcription not only ex vivo in peripheral blood mononuclear cells from aviremic HIV-1-infected donors receiving combined antiretroviral therapy but also in vitro in cells of myeloid-monocytic origin targeting the NF-κB and mitogen-activated protein kinase pathways. Interestingly, the activation marker CD69 was significantly upregulated in natural killer (NK) cells, B cells, and monocytes 48 h after SMU-Z1 treatment. Furthermore, SMU-Z1 was able to activate T cells without global T cell activation, as well as increasing NK cell degranulation and gamma interferon (IFN-γ) production, which further block HIV-1-infected CD4+ lymphocytes. In summary, the present study found that SMU-Z1 can both enhance HIV-1 transcription and promote NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells. These findings indicate that the novel TLR1/2 agonist SMU-Z1 is a promising latency-reversing agent (LRA) for eradication of HIV-1 reservoirs. IMPORTANCE Multiple in vivo studies showed that many LRAs used in the shock-and-kill approach could activate viral transcription but could not induce killing effectively. Therefore, a dual-function LRA is needed for elimination of HIV-1 reservoirs. We previously developed a small-molecule TLR1/2 agonist, SMU-Z1, and demonstrated that it could upregulate NK cells and CD8+ T cells with immune adjuvant and antitumor properties in vivo. In the present study, SMU-Z1 could activate innate immune cells without global T cell activation, induce production of proinflammatory and antiviral cytokines, and enhance the cytotoxic function of NK cells. We showed that SMU-Z1 displayed dual potential ex vivo in the shock of exposure of latently HIV-1-infected cells and in the kill of clearance of infected cells, which is critical for effective use in combination with therapeutic vaccines or broadly neutralizing antibody treatments aimed at curing AIDS.

7.
Transplant Cell Ther ; 27(4): 344.e1-344.e5, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836888

RESUMO

Polypharmacy is common in older adults with cancer, but there is little evidence evaluating the impact of polypharmacy and other medication hazards on allogeneic hematopoietic cell transplantation (alloHCT) outcomes. A small number of prior studies have evaluated the impact of potentially inappropriate medication (PIM) use in the setting of alloHCT, with mixed results. We evaluated the effects of pre-alloHCT polypharmacy, PIM use, and drug-drug interactions (DDIs) on post-alloHCT outcomes, including overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), hospital length of stay (LOS), number of non-hematologic grade ≥3 adverse events (AEs) within 100 days after alloHCT, and number of readmissions within the first 100 days after alloHCT. The study population was a single-center prospective cohort of 148 patients ≥ 50 years of age. Pre-alloHCT medication lists were retrospectively collected from the electronic medical record, including both scheduled and as-needed medications. PIMs were defined by a modified 2019 American Geriatrics Society Beers Criteria. DDIs were analyzed using Lexi-Interact. Polypharmacy was common in this population; the median number of medications was seven (range, 0 to 23). Fifty-two patients (35%) were prescribed nine or more medications, and 73 patients (49%) had at least one PIM prescribed. The median number of DDIs was three (range, 0 to 31), and the most common severity was major (48%). After adjusting for age and Hematopoietic Cell Transplant Comorbidity Index (HCTCI), both the number of all medications and number of scheduled medications were associated with inferior OS, with hazard ratios (HRs) of 1.07 (95% confidence interval [CI], 1.01 to 1.12; P = .02) and 1.08 (95% CI, 1.00 to 1.15; P = .04), respectively. Receipt of nine or more scheduled medications was associated with inferior OS (HR, 1.92; 95% CI, 1.11 to 3.32; P = .02). The number of PIMs was also significantly associated with OS (HR, 1.24; 95% CI, 1.00 to 1.54, P = .05). After adjusting for age, HCTCI, and total number of medications, a greater number of DDIs were significantly associated with longer hospital length of stay (difference, 0.74 days; 95% CI, 0.09 to 1.40, P = .03). In adjusted analyses, there were no significant polypharmacy-related predictors of NRM, LOS, or non-hematologic grade ≥3 AEs. These data demonstrate the utility of pre-alloHCT polypharmacy, PIM use, and DDIs as important prognostic factors and support routine pre-alloHCT medication review by physicians and pharmacists with a goal of appropriate de-prescribing where possible.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Polimedicação , Idoso , Humanos , Prescrição Inadequada , Recidiva Local de Neoplasia , Estudos Prospectivos , Estudos Retrospectivos , Estados Unidos
8.
Support Care Cancer ; 29(9): 5399-5408, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33694088

RESUMO

PURPOSE: Patients with non-Hodgkin lymphoma (NHL) have a median age of 67, with 70% surviving over 5 years. Chemotherapy for aggressive NHL includes cyclophosphamide, anthracycline, and high doses of corticosteroids, which can impair bone health. By reviewing clinical characteristics and standard-of-care CT scans, we evaluate the prevalence and incidence of fractures and the clinical correlates of fractures in patients treated for aggressive B-cell NHL. METHODS: We retrospectively reviewed patients seen at the University of California San Francisco lymphoma clinic from January 1, 2016, to March 31, 2017 who had (1) aggressive B-cell NHL, (2) received first-line therapy with R-CHOP-like regimens, and had (3) CT scans pre- and post-treatment available for review. Associations between clinical variables and vertebral, rib, and pelvic fracture outcomes were assessed, and multivariate logistic regression models were used to identify predictors of prevalent and incident fractures. RESULTS: We identified 162 patients who met the inclusion criteria. Median age at diagnosis was 60 years. Of the 162 patients, 38 patients (28%) had prevalent fractures prior to receiving chemotherapy. Within 1 year after treatment, 16 patients (10%) developed new fractures. Having a prevalent fracture strongly predicted developing a new fracture after treatment, with incident fractures occurring in 12 of 38 patients with prevalent fractures versus 4 of 124 without prevalent fractures (odds ratio 10.45, p<0.0005). CONCLUSION: Our results suggest that patients with aggressive B-cell NHL who receive R-CHOP-like therapy should be screened for fractures prior to treatment and those with existing fractures should be considered for therapy to decrease risk of new fractures.

9.
Nat Commun ; 12(1): 960, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574252

RESUMO

Nitric oxide (NO) is an important signaling molecule overexpressed in many diseases, thus the development of NO-activatable probes is of vital significance for monitoring related diseases. However, sensitive photoacoustic (PA) probes for detecting NO-associated complicated diseases (e.g., encephalitis), have yet to be developed. Herein, we report a NO-activated PA probe for in vivo detection of encephalitis by tuning the molecular geometry and energy transformation processes. A strong donor-acceptor structure with increased conjugation can be obtained after NO treatment, along with the active intramolecular motion, significantly boosting "turn-on" near-infrared PA property. The molecular probe exhibits high specificity and sensitivity towards NO over interfering reactive species. The probe is capable of detecting and differentiating encephalitis in different severities with high spatiotemporal resolution. This work will inspire more insights into the development of high-performing activatable PA probes for advanced diagnosis by making full use of intramolecular motion and energy transformation processes.


Assuntos
Técnicas Biossensoriais/métodos , Encefalite/diagnóstico , Encefalite/metabolismo , Óxido Nítrico/isolamento & purificação , Técnicas Fotoacústicas/métodos , Animais , Técnicas Biossensoriais/instrumentação , Modelos Animais de Doenças , Encefalite/patologia , Masculino , Camundongos , Imagem Molecular/métodos , Sondas Moleculares/química , Técnicas Fotoacústicas/instrumentação
10.
Acta Cardiol Sin ; 36(6): 641-648, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33235421

RESUMO

Background: Sudden cardiac death (SCD) is an uncommon but significant cause of death in the young. Citywide cardiac screening of school-aged children has been performed in Taipei since 1989. In this study, we investigate the efficacy of this screening method for identifying those at high risk of SCD. Methods: This study analyzed the data from the results of cardiac screening for school-aged children in Taipei from 2003 to 2014. The cardiac screening included: Stage I, questionnaire surveys, simplified phonocardiography test and simplified electrocardiography (ECG) test; Stage II, physical examination and auscultation by a pediatric cardiologist for all children who had abnormal findings in stage I screening; Stage III, referral to a pediatric cardiologist for further examinations. Logistic regression and decision tree analyses were performed. Results: A total of 566,447 students were screened, of whom 685 were identified as being at high risk of SCD. The most common causes of being at high risk of SCD included Wolff-Parkinson-White syndrome, long QT syndrome, cardiomyopathy and Marfan's syndrome. Using logistic regression analysis, the simplified ECG test was identified as being the most effective tool (odds ratio = 16.4, p < 0.001) and past history as the second most crucial factor (odds ratio = 3.95, p < 0.001) for detecting a high risk of SCD. Decision tree analysis showed that serial studies with a past history and the simplified ECG test could accurately identify those at high risk of SCD. Conclusions: Questionnaire survey and simplified electrocardiography test-based cardiovascular screening in school-aged children can identify those at high risk of SCD.

11.
Wei Sheng Yan Jiu ; 49(5): 802-808, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070815

RESUMO

OBJECTIVE: To investigate the effects of electrolytic drinking water on the hyperuricemia and the potential mechanism. METHODS: The 6-week-old SD rats were induced as the animal model with hyperuricemia by yeast extract(10 g/kg) and adenine(100 g/kg) gavage(twice per day) combined with oxygen oxazine acid potassium(300 mg/kg, the 1~(st), 5~(th) and 10~(th )day) i. p. Then the rats were supplied electrolytic drinking water in different dosages(1 mL, 2 mL and 3 mL) by gavage for 7 days. Weight was measured at regular intervals. The 24-hour urine was sampled by metabolic cage for the measurements of uric acid, creatinine and urea nitrogen levels. The parameters for the uric acid clearance were calculated. The serum was sampled after execution for the determination of serum uric acid, creatinine. The activities of xanthine oxidase and adenine dehydrogenase were detected. The morphological measurements of stomach and kidney were completed. RESULTS: The hyperuricemia model was successfully induced by this method. In the intervention, the pH of urine was significantly elevated along with the electrolytic drinking water intake(P<0. 01). The excretion of uric acid in the rats with hyperuricemia was significantly increased while administrated with electrolytic drinking water. The effects of improving uric acid excretion were enhanced along with the intake of electrolytic drinking water. The levels of serum uric acid(group Model, Model+Treatment 1, Model+Treatment 2 and Model+Treatment 3: 693. 7 µmol/L, 668. 1 µmol/L, 642. 5 µmol/L, 633. 1 µmol/L), urine uric acid(5740. 0 µmol/L, 5894. 1 µmol/L, 5562. 3 µmol/L, 5083. 2 µmol/L) and urea nitrogen(11. 40 mmol/L, 10. 47 mmol/L, 9. 54 mmol/L, 8. 93 mmol/L) were significantly decreased in the model rats with high dose intervention(P<0. 05). Clearance of uric acid was obviously increased(9. 27%, 10. 40%, 10. 44%, 11. 13%, P<0. 05). However, no pathological change was observed among the three groups with intervention. CONCLUSION: The electrolytic drinking water intake is benefit for the excretion of uric acid of hyperuricemia rat. Enhancing alkalization of urine is considered as the important mechanism of the beneficial effects.


Assuntos
Água Potável , Hiperuricemia , Animais , Creatinina , Hiperuricemia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Ácido Úrico
12.
Cancer ; 127(1): 124-136, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997342

RESUMO

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen-deprivation therapy, is unknown. METHODS: Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all-cause bacterial pneumonia hospitalizations was analyzed. RESULTS: Over 7 years of follow-up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person-years versus 162.0 per 1000 person-years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia-related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23-vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001). CONCLUSIONS: Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival.

13.
J Am Chem Soc ; 142(32): 13756-13767, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32686406

RESUMO

ß-Lactamase inhibitory protein (BLIP) can effectively inactivate class A ß-lactamases, but with very different degrees of potency. Understanding the different roles of BLIP in class A ß-lactamases inhibition can provide insights for inhibitor design. However, this problem was poorly solved on the basis of the static structures obtained by X-ray crystallography. In this work, ion mobility mass spectrometry, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics simulation revealed the conformational dynamics of three class A ß-lactamases with varying inhibition efficiencies by BLIP. A more extended conformation of PC1 was shown compared to those of TEM1 and SHV1. Localized dynamics differed in several important loop regions, that is, the protruding loop, H10 loop, Ω loop, and SDN loop. Upon binding with BLIP, these loops cooperatively rearranged to enhance the binding interface and to inactivate the catalytic sites. In particular, unfavorable changes in conformational dynamics were found in the protruding loop of SHV1 and PC1, showing less effective binding. Intriguingly, the single mutation on BLIP could compensate for the unfavored changes in this region, and thus exhibit enhanced inhibition toward SHV1 and PC1. Additionally, the H10 region was revealed as an important allosteric site that could modulate the inhibition of class A ß-lactamases. It was suggested that the rigid protruding loop and flexible H10 region might be determinants for the effective inhibition of TEM1. Our findings provided unique and explicit insights into the conformational dynamics of ß-lactamases and their bindings with BLIP. This work can be extended to other ß-lactamases of interest and inspire the design of novel inhibitors.


Assuntos
Proteínas de Bactérias/metabolismo , Simulação de Dinâmica Molecular , beta-Lactamases/metabolismo , Proteínas de Bactérias/química , Sítios de Ligação , Cristalografia por Raios X , Conformação Molecular , Streptomyces/química
14.
BMC Infect Dis ; 20(1): 462, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611396

RESUMO

BACKGROUND: At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China. METHODS: The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed. RESULTS: As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p < 0.001). Three genomic clusters, each with genomic distance ≤12 SNPs, were identified with 2, 3 and 4 consanguineous strains. Two clusters were from hot spots and one was from cold spots. CONCLUSION: Narrower genotype diversity in the hot area may indicate higher transmissibility of the Mtb strains in the area compared to those in the cold spot area.


Assuntos
Temperatura Baixa , Epidemias , Temperatura Alta/efeitos adversos , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , China/epidemiologia , Análise por Conglomerados , Genótipo , Humanos , Incidência , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Polimorfismo de Nucleotídeo Único , Escarro/microbiologia , Tuberculose Pulmonar/transmissão , Sequenciamento Completo do Genoma
15.
Blood Adv ; 4(12): 2810-2820, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32574365

RESUMO

Use of allogeneic hematopoietic cell transplantation (alloHCT) is increasing in older patients with hematologic malignancies. Studies suggest that geriatric assessment (GA), incorporating functional measures such as instrumental activities of daily living (IADL), delineates subtle age-related impairments that enhance risk-stratification. The objective of this multi-institutional retrospective study was to evaluate the prognostic utility of GA metrics collected pre-alloHCT. Eligibility criteria included age ≥50 and pre-alloHCT GA inclusive of at least IADL. Beyond IADL, additional geriatric metrics were collected where available and included Medical Outcomes Study Physical Health score (MOS-PH), Timed Up and Go (TUG), and cognition by Blessed Orientation Memory Concentration (BOMC). Three hundred thirty subjects were included, with a median age of 63 (range 50 to 77). Impairments were frequent: 36% had at least 1 IADL impairment; 14% had TUG ≥13.5 seconds; and 17% had cognitive impairment (BOMC ≥ 7). Median MOS-PH score was 80. IADL and age were not significantly associated with nonrelapse mortality (NRM) or overall survival (OS). In multivariate analysis, only impaired cognition and Hematopoietic Cell Transplant-Comorbidity Index score ≥3 showed an independent association with 1-year NRM (subdistribution hazard ratio [SHR], 2.36; P = .01; and SHR, 2.19; P = .009, respectively). Cognitive impairment independently conferred inferior 1-year OS (hazard ratio, 1.94; P = .01). In a preplanned subgroup analysis in 224 patients aged ≥60 years, cognitive impairment remained the sole GA metric predictive of NRM (2-year NRM: SHR, 2.72; P = .007). These data suggest that cognitive impairment elevates risk of post-alloHCT NRM in older patients.


Assuntos
Disfunção Cognitiva , Transplante de Células-Tronco Hematopoéticas , Atividades Cotidianas , Idoso , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Avaliação Geriátrica , Humanos , Estudos Retrospectivos
16.
J Viral Hepat ; 27(8): 826-836, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32187804

RESUMO

The performances of routine tests such as FIB-4 and APRI in detecting cirrhosis and significant fibrosis in chronic hepatitis B (CHB) have been shown to be discrepant between studies. Novel tests such as red cell distribution width-platelet ratio (RPR), γ-glutamyl transpeptidase to platelet ratio (GPR) and easy liver fibrosis test (eLIFT) are introduced recently. To evaluate the aminotransferase influence on the performance of these routine tests, a total of 1005 CHB patients who underwent liver biopsies and routine tests were retrospectively analysed. The diagnostic cut-offs referring to likelihood ratio were determined for excluding or including cirrhosis diagnosis and also for ruling in significant fibrosis diagnosis. The performances of RPR, FIB-4, eLIFT and APRI in detecting cirrhosis seemed improved at higher ALT levels, while GPR was conversely impaired. The likelihood ratio was âˆ for APRI cut-off 2 diagnosing cirrhosis in ALT < 2 upper limit of normal (ULN), 14.6 for APRI cut-off 1.5 determining significant fibrosis in ALT ≤ 5ULN and 20.6 for FIB-4 cut-off 3.2 diagnosing ≥ F3 in the total cohort, respectively. The optimal cut-offs for cirrhosis diagnosis were increased with higher ALTs by tests which included aminotransferase, but not for RPR. The proportions of patients classified as having cirrhosis or no cirrhosis stratified by ALT level cut-offs were superior. Stepwise applying RPR, GPR and eLIFT would determine 60% of patients as having cirrhosis or no cirrhosis with an accuracy of 93.0%. In conclusion, the performance of aminotransferase comprising tests in detecting cirrhosis in CHB were influenced by ALT levels. Thus, ALT stratified cut-offs may be a preferred alternative. In resource-limited settings, stepwise applying routine tests could be recommended as a preferred measurement for cirrhosis detection.

17.
Front Cardiovasc Med ; 7: 16, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32154267

RESUMO

Radiotherapy (RT) is a crucial treatment modality in managing cancer patients. However, irradiation dose sprinkling to tumor-adjacent normal tissues is unavoidable, generating treatment toxicities, such as radiation-associated cardiovascular dysfunction (RACVD), particularly for those patients with combined therapies or pre-existing adverse features/comorbidities. Radiation oncologists implement several efforts to decrease heart dose for reducing the risk of RACVD. Even applying the deep-inspiration breath-hold (DIBH) technique, the risk of RACVD is though reduced but still substantial. Besides, available clinical methods are limited for early detecting and managing RACVD. The present study reviewed emerging challenges of RACVD in modern radiation oncology, in terms of clinical practice, bench investigation, and multidisciplinary care. Several molecules are potential for serving as biomarkers and therapeutic targets. Of these, miRNAs, endogenous small non-coding RNAs that function in regulating gene expression, are of particular interest because low-dose irradiation, i.e., 200 mGy (one-tenth of conventional RT daily dose) induces early changes of pro-RACVD miRNA expression. Moreover, several miRNAs, e.g., miR-15b and miR21, involve in the development of RACVD, further demonstrating the potential bio-application in RACVD. Remarkably, many RACVDs are late RT sequelae, characterizing highly irreversible and progressively worse. Thus, multidisciplinary care from oncologists and cardiologists is crucial. Combined managements with commodities control (such as hypertension, hypercholesterolemia, and diabetes), smoking cessation, and close monitoring are recommended. Some agents show abilities for preventing and managing RACVD, such as statins and angiotensin-converting enzyme inhibitors (ACEIs); however, their real roles should be confirmed by further prospective trials.

18.
Biol Blood Marrow Transplant ; 26(1): 189-196, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493541

RESUMO

Allogeneic hematopoietic cell transplantation (alloHCT) has been increasingly offered to older adults with hematologic malignancies. However, optimal methods to determine fitness for alloHCT have yet to be defined. We evaluated the ability of a comprehensive geriatric assessment (CGA) to predict post-alloHCT outcomes in a single-center prospective cohort study of patients age 50 years and older. Outcomes included overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM). A total of 148 patients were included, with a median age of 62 years (range, 50 to 76 years). In multivariate regression analysis, several CGA measures of functional status were predictive of post-alloHCT outcomes, after adjusting for traditional prognostic factors. Any deficit in instrumental activities of daily living (IADL) was associated with inferior OS (hazard ratio [HR], 1.81, 95% confidence interval [CI], 1.07 to 3.08; P = .03) and PFS (HR, 1.85; 95% CI, 1.15 to 2.99; P = .01). A Medical Outcomes Study Physical Health scale (MOS-PH) score <85 was associated with inferior OS (HR, 1.96; 95% CI, 1.13 to 3.40; P = .02), PFS (HR, 1.75; 95% CI, 1.07 to 2.88; P = .03), and increased NRM (subdistribution HR, 2.57; 95% CI, 1.12 to 5.92; P = .03). MOS-PH score was also associated with the number of non-hematologic grade ≥3 adverse events within the first 100 days after alloHCT (rate ratio, 1.61; 95% CI, 1.04 to 2.49; P = .03). These findings support previous work suggesting that IADL is an important prognostic tool prior to alloHCT. MOS-PH is newly identified as an additional metric to identify older patients at higher risk of poor post-alloHCT outcomes, including toxicity and NRM.


Assuntos
Atividades Cotidianas , Avaliação Geriátrica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
19.
Br J Sports Med ; 54(10): 582-591, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31296585

RESUMO

BACKGROUND: Few studies have examined the associations between physical activity (PA), sedentary behaviour (SB) and risk of colorectal neoplasia (CN). METHODS: We systematically searched Medline, Embase, PsyInfo, Cochrane and other sources from their inception to 30 September 2018 for cohort, case-control and cross-sectional studies that evaluated these associations in asymptomatic, average-risk subjects. Random-effect models were used to estimate relative risks (RRs) of any-type CN, advanced CN, and non-advanced CN, respectively, in individuals with the highest versus the lowest level of PA and SB. Dose-response analyses and subgroup analyses were conducted. The I2 statistic was used to examine heterogeneity among studies. RESULTS: We identified 32 observational studies, including 17 cross-sectional studies, 10 case-control studies and five longitudinal studies. PA (highest vs lowest) was inversely associated with risk for any-type CN (n=23 studies) and advanced CN (n=15 studies), with a RR of 0.77 (95% CI=0.71 to 0.83, I2=57.5%) and 0.73 (95% CI=0.63 to 0.82, I2=45.5%), respectively. There was no association between PA and non-advanced CN (n=5 studies). There was an as association between PA and any-type CN in both sexes, and also for the distal colon. We found no dose-response relationship between PA and any-type or advanced CN. Based on three studies identified, SB time (longest vs shortest) was associated with an increased risk of advanced CN (RR=1.24, 95% CI 1.04 to 1.49, I2=14.4%). No publication bias was detected by Begg's test. CONCLUSION: We report a 23% lower relative risk of any type of CN and a 27% lower risk of advanced CN in people with the highest level of PA compared with those in the lowest.


Assuntos
Neoplasias Colorretais/epidemiologia , Exercício Físico , Comportamento Sedentário , Estilo de Vida Saudável , Humanos , Prevalência , Fatores de Risco , Distribuição por Sexo
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