Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 236
Filtrar
1.
Drug Alcohol Rev ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34636100

RESUMO

INTRODUCTION: Injection drug use initiation is commonly facilitated by other people who inject drugs (PWID). We investigated how the gender of PWID influences their risk of providing initiation assistance to others across two distinct geo-cultural settings. METHODS: Data were drawn from two prospective cohorts in Tijuana, Mexico and Vancouver, Canada which conducted semi-annual interviews within the PReventing Injecting by Modifying Existing Responses (PRIMER) study. Participants consisted of PWID who had reported never providing injection initiation assistance at baseline. We then conducted site-specific discrete-time survival analyses assessing the relationship between gender and other relevant covariates (e.g. age and past 6-month sex work) on the risk of the first reported instance of providing initiation assistance. RESULTS: Of 1988 PWID (Tijuana: n = 596; Vancouver: n = 1392), 256 (43%) and 511 (36.7%) participants were women, and 42 (1.7%) and 78 (1.6%) reported recent injection initiation assistance across a median of three and two follow-up visits, respectively. Women had a lower risk of providing injection initiation assistance for the first time in Tijuana (adjusted hazard ratio = 0.52, 95% confidence interval 0.27-0.99), but not in Vancouver. Gendered pathways, like sex work, were associated with providing initiation assistance for the first time in Vancouver (adjusted hazard ratio = 1.97, 95% confidence interval 1.08-3.61). DISCUSSION AND CONCLUSIONS: Women in Tijuana, but not Vancouver, were less likely to provide first-time initiation assistance among PWID. These results can inform gender- and site-specific prevention efforts aimed at reducing transitions into drug injecting across geographic contexts.

2.
Cancer Cell ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34653365

RESUMO

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ T cells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ T cells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ T cells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.

3.
JAMA Netw Open ; 4(9): e2126626, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34570207

RESUMO

Importance: Anger is linked to adverse outcomes in military populations; however, whether pre-enlistment anger attacks are associated with postenlistment mental disorders and suicidality is unknown. Objective: To explore the associations of pre-enlistment anger attacks with postenlistment mental health. Design, Setting, and Participants: In this observational cohort study, the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) New Soldier Study (NSS) surveyed soldiers entering basic training from April 2011 to November 2012, with a subsample recruited for wave 1 of the STARRS Longitudinal Study (STARRS-LS) (conducted September 2016 to April 2018). Participants were recruited from 3 US Army installations for the NSS survey. Those who were subsequently contacted for STARRS-LS completed the follow-up survey via web or telephone. Prospective analyses were based on a weighted NSS subsample included in wave 1 of STARRS-LS. Data were analyzed from May 22, 2020, to March 17, 2021. Exposures: History of anger attacks at baseline (NSS). Survey responses were used to classify new soldiers as having nonimpairing anger attacks (>2 attacks without interference in work or personal life), impairing anger attacks (>2 attacks with interference in work or personal life), or no significant history of anger attacks. Main Outcomes and Measures: Baseline analyses examined sociodemographic and clinical correlates of a history of anger attacks. Prospective logistic regression models estimated associations of baseline history of anger attacks with new onset and persistence of posttraumatic stress disorder, major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, mania/hypomania, substance use disorder, suicidal ideation, and suicide attempt at wave 1 of STARRS-LS. Results: Of the 38 507 baseline participants (83.0% male and 17.0% female; mean [SD] age, 20.97 [3.57] years), 6216 were selected for and completed wave 1 of the STARRS-LS. Baseline prevalence (SE) of nonimpairing and impairing anger attacks was 8.83% (0.16%) and 5.75% (0.15%), respectively. Prospective models showed that impairing anger attacks were associated with new onset of MDD (adjusted odds ratio [AOR], 1.98; 95% CI, 1.31-2.99), GAD (AOR, 2.39; 95% CI, 1.66-3.45), panic disorder (AOR, 2.02; 95% CI, 1.34-3.05), and suicidal ideation (AOR, 2.11; 95% CI, 1.45-3.07). When baseline psychiatric comorbidity was controlled for, impairing attacks remained associated with onset of GAD (AOR, 1.75; 95% CI, 1.19-2.58) and suicidal ideation (AOR, 1.62; 95% CI, 1.09-2.42). Anger attacks were not significantly associated with persistence of pre-enlistment mental disorders. Conclusions and Relevance: The findings of this study suggest that a pre-enlistment history of impairing anger attacks may be associated with elevated risk of developing GAD, MDD, and suicidality after enlistment. Detection of impairing anger attacks could aid in assessing psychiatric risk in new soldiers.

4.
Medicine (Baltimore) ; 100(34): e27047, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449491

RESUMO

ABSTRACT: Evaluate the impact of switching to an anti-retroviral regimen containing tenofovir alafenamide (TAF) on weight and the development of metabolic complications compared to remaining on a non-TAF containing regimen.Single-center retrospective case-control study.We evaluated people living with human immunodeficiency virus (PLWH) who were on an anti-retroviral regimen not containing TAF and were switched to a regimen containing TAF between January 1, 2016 and September 30, 2018. The control group included PLWH on a TAF free regimen throughout the study period. The primary outcome was change in weight from baseline to 12 months postswitch. Secondary outcomes included percent change in weight, change in body mass index (BMI), change in BMI class, and new diagnoses of diabetes, hypertension, and hyperlipidemia (HLD) during the study period.PLWH switched to TAF (n = 446) demonstrated significantly greater mean increase in weight compared to the control group (n = 162) (1.97 vs 0.88 kg, P = .01), however the effect was only seen in those switched from tenofovir disoproxil fumarate. Those that switched to TAF also had a significantly higher percent increase in weight, increase in BMI, and BMI class. We observed a higher rate of new diagnosis of HLD in the control group compared to the TAF switch group during the study period.PLWH switched to TAF had greater increases in weight after 1 year as compared to those continuing on a TAF free regimen. However, this did not translate to higher rates of obesity related illnesses such as diabetes, hypertension, and HLD during the follow up period.


Assuntos
Alanina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Tenofovir/análogos & derivados , Ganho de Peso/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Índice de Massa Corporal , Estudos de Casos e Controles , Comorbidade , Feminino , Infecções por HIV , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tenofovir/uso terapêutico
5.
J Neurotrauma ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34435894

RESUMO

It is important to measure quality of life (QoL) after traumatic brain injury (TBI), yet limited studies have compared QoL inventories. In 2579 TBI patients, orthopedic trauma controls, and healthy friend control participants, we compared the Quality of Life After Brain Injury-Overall Scale (QOLIBRI-OS), developed for TBI patients, to the Satisfaction with Life Scale (SWLS), an index of generic life satisfaction. We tested the hypothesis that group differences (TBI and orthopedic trauma vs. healthy friend controls) would be larger for the QOLIBRI-OS than the SWLS and that the QOLIBRI-OS would manifest more substantial changes over time in the injured groups, demonstrating more relevance of the QOLIBRI-OS to traumatic injury recovery. (1) We compared the group differences (TBI vs. orthopedic trauma control vs. friend control) in QoL as indexed by the SWLS versus the QOLIBRI-OS and (2) characterized changes across time in these two inventories across 1 year in these three groups. Our secondary objective was to characterize the relationship between TBI severity and QoL. As compared with healthy friend controls, the QOLIBRI reflected greater reductions in QoL than the SWLS for both the TBI group (all time points) and the orthopedic trauma control group (2 weeks and 3 months). The QOLIBRI-OS better captured expected improvements in QoL during the injury recovery course in injured groups than the SWLS, which demonstrated smaller changes over time. TBI severity was not consistently or robustly associated with self-reported QoL. The findings imply that, as compared with the SWLS, the QOLIBRI-OS appears to identify QoL issues more specifically relevant to traumatically injured patients and may be a more appropriate primary QoL outcome measure for research focused on the sequelae of traumatic injuries.

6.
Int J Drug Policy ; 95: 103398, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34390966

RESUMO

BACKGROUND: Individuals who initiate injection drug use often receive assistance from an injection-knowledgeable peer. Persons who assist peers in injection initiation events often inject frequently, which heightens overdose risk. As such, overdose and injection initiation events may be correlated. To explore a potential relationship, we assessed temporal associations between experiencing a non-fatal overdose and assisting others in initiating injection drug use among persons who inject drugs in two North American cities - Vancouver, Canada and Tijuana, Mexico. METHODS: From 2014 to 2018, this retrospective cohort study included people who inject drugs from Vancouver (n=1332) and Tijuana (n=666) who completed a baseline and six-month follow-up interview. Within each site, we assessed bidirectional temporal associations using two separate multivariable logistic regression models: for model 1, recent provision of injection initiation assistance (at six months) was the outcome and recent overdose (at baseline) was the exposure; for model 2, recent overdose (at six months) was the outcome and recent provision of injection initiation assistance (at baseline) was the exposure. Both models adjusted for potential confounders. RESULTS: Vancouver-based participants reporting overdose at baseline had 163% greater odds of reporting provision of injection initiation assistance at follow-up (adjusted Odds Ratio [aOR] 2.63; 95% Confidence Interval [CI] 1.41-4.90); while participants reporting provision of injection initiation assistance at baseline had 89% greater odds of reporting a non-fatal overdose at follow-up (aOR 1.89; 95% CI 1.00-3.57). Among Tijuana-based participants, we did not observe a statistically significant association in either direction. CONCLUSION: Findings in Vancouver suggest that injection initiation assistance and overdose are bidirectionally-associated phenomena. The present findings highlight the need for interventions that ensure that persons who provide injection initiation assistance are given overdose prevention support, both for themselves and for those they assist to initiate injection drug use. While our Tijuana-based results did not suggest a bidirectional relationship, preventative approaches should nonetheless be undertaken.

7.
Foodborne Pathog Dis ; 18(8): 599-606, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34403268

RESUMO

Salmonella is a global foodborne pathogen that causes human diseases ranging from mild gastroenteritis to severe systemic infections. Recently, antimicrobial blue light (aBL) showed effective bactericidal activity against a variety of bacteria (e.g., Salmonella) with varying efficiency. However, the antimicrobial mechanism of aBL has not been fully elucidated. Our previous report showed that the outer membrane (OM) is a key target of aBL. The major component of the OM, lipopolysaccharide (LPS), may play a role in aBL bactericidal effect. Therefore, the influence of LPS truncation on the sensitivity of Salmonella Typhimurium SL1344 to aBL was investigated for the first time. First, the rfaC gene in the SL1344 strain likely involved in linking lipid A to the core region of LPS was inactivated and the influence on LPS structure was verified in the mutant strain SL1344ΔrfaC. SL1344ΔrfaC showed a significant increase in sensitivity to aBL, and the bactericidal efficiency exceeded 8 log CFU at an aBL dose of 383 J/cm2, while that of its parental SL1344 strain approached 4 log CFU. To discover the possible mechanism of higher sensitivity, the permeability of OM was determined. Compared to SL1344, SL1344ΔrfaC showed 2.7-fold higher permeability of the OM at 20 J/cm2, this may explain the higher vulnerability of the OM to aBL. Furthermore, the fatty acid profile was analyzed to reveal the detailed changes in the OM and inner membrane of the mutant. Results showed that the membrane lipids of SL1344ΔrfaC were markedly different to SL1344, indicating that change in fatty acid profile might mediate the enhancement of OM permeability and the increased sensitivity to aBL in SL1344ΔrfaC. Hence, we concluded that disruption of rfaC in Salmonella Typhimurium led to the formation of truncated LPS and thus enhanced the permeability of the OM, which contributed to the increased sensitivity to aBL.

8.
Cell Biosci ; 11(1): 159, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399835

RESUMO

BACKGROUND: Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. METHODS: In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. RESULTS: Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, ß-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/ß-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA­PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification. CONCLUSION: The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

9.
BMJ Open ; 11(8): e046957, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385244

RESUMO

OBJECTIVES: People who inject drugs (PWID) play an integral role in facilitating the entry of others into injection drug use (IDU). We sought to assess factors influencing PWID in providing IDU initiation assistance across three distinct North American settings and to generate pooled measures of risk. DESIGN: We employed data from three PWID cohort studies participating in PReventing Injecting by Modifying Existing Responses (PRIMER), for this cross-sectional analysis. SETTING: Tijuana, Mexico; San Diego, USA; Vancouver, Canada. PARTICIPANTS: A total of 2944 participants were included in this study (Tijuana: n=766, San Diego: n=353, Vancouver: n=1825). MEASUREMENTS: The outcome was defined as recently (ie, past 6 months) assisting in an IDU initiation event. Independent variables of interest were identified from previous PRIMER analyses. Site-specific multiple modified Poisson regressions were fit. Pooled relative risks (pRR) were calculated and heterogeneity across sites was assessed via linear random effects models. RESULTS: Evidence across all three sites indicated that having a history of providing IDU initiation assistance (pRR: 4.83, 95% CI: 3.49 to 6.66) and recently being stopped by law enforcement (pRR: 1.49, 95% CI: 1.07 to 2.07) were associated with a higher risk of providing assistance with IDU initiation; while recent opioid agonist treatment (OAT) enrolment (pRR: 0.64, 95% CI: 0.43 to 0.96) and no recent IDU (pRR: 0.21, 95% CI: 0.07 to 0.64) were associated with a lower risk. We identified substantial differences across site in the association of age (I2: 52%), recent housing insecurity (I2: 39%) and recent non-injection heroin use (I2: 78%). CONCLUSION: We identified common and site-specific factors related to PWID's risk of assisting in IDU initiation events. Individuals reporting a history of assisting IDU initiations, being recently stopped by law enforcement, and recently injecting methamphetamine/speedball were more likely to have recently assisted an IDU initiation. Whereas those who reported not recently engaging in IDU and those recently enrolled in OAT were less likely to have done so. Interventions and harm reduction strategies aimed at reducing the harms of IDU should incorporate context-specific approaches to reduce the initiation of IDU.


Assuntos
Preparações Farmacêuticas , Abuso de Substâncias por Via Intravenosa , Estudos de Coortes , Estudos Transversais , Humanos , México/epidemiologia , Abuso de Substâncias por Via Intravenosa/epidemiologia
10.
Drug Alcohol Depend ; 225: 108829, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34237582

RESUMO

OBJECTIVE: To assess the relationship between experiencing homelessness and assisting injection drug use (IDU) initiation among people who inject drugs (PWID) in Tijuana, Mexico and Vancouver, Canada. METHODS: We used self-reported questionnaire data collected semi-annually on PWID from Tijuana (n = 703) and Vancouver (n = 1551) between 2014 and 2017. Within each setting, the effect of recent (i.e., past six months) homelessness on recent provision of injection initiation assistance (i.e., helping anybody inject for the first time in the past six months) was estimated using inverse-probability-of-treatment (IPT)-weighted estimation of a marginal structural model. RESULTS: Across follow-up, the prevalence of recent homelessness at a given visit ranged from 11.6%-16.5% among Tijuana-based participants and 9.4%-18.9% among Vancouver-based participants; the prevalence of recent provision of injection initiation at a given follow-up visit was lower, ranging from 3.3%-5.4% in Tijuana and 2.5%-4.1% in Vancouver. Based on the IPT-weighted estimates, recent homelessness was associated with 66% greater odds among Tijuana-based PWID (Adjusted Odds Ratio [AOR] = 1.66; 95% CI: 1.01-2.73) and 47% greater odds among Vancouver-based PWID (AOR = 1.47, 95% CI: 1.02-2.13) of providing injection initiation assistance over the same six-month period. CONCLUSION: We found that recently experiencing homelessness was associated with an increased likelihood of PWID reporting IDU initiation assistance over time in both Tijuana and Vancouver. Addressing homelessness may decrease the initiation of IDU via multiple pathways.


Assuntos
Usuários de Drogas , Pessoas em Situação de Rua , Preparações Farmacêuticas , Abuso de Substâncias por Via Intravenosa , Canadá/epidemiologia , Humanos , México/epidemiologia , Abuso de Substâncias por Via Intravenosa/epidemiologia
11.
JAMA Neurol ; 78(9): 1137-1148, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279565

RESUMO

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective: To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures: Acute nonpenetrating head trauma. Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months. Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study. Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.

12.
Cancer Sci ; 112(9): 3585-3597, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252986

RESUMO

Diffuse large B cell lymphoma (DLBCL) heterogeneity promotes recurrence and anti-CD20-based therapeutic resistance. Previous studies have shown that downregulation of MS4A1/CD20 expression after chemoimmunotherapy with rituximab leads to rituximab resistance. However, the mechanisms of CD20 loss remain unknown. We identified that pyruvate dehydrogenase kinase 4 (PDK4) is markedly elevated in DLBCL cells derived from both patients and cell lines with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance. We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression. Collectively, this is the first study showing that targeting PDK4 has the potential to overcome rituximab resistance in DLBCL.


Assuntos
Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/administração & dosagem , Reprogramação Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glicoproteínas/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Rituximab/administração & dosagem , Transdução de Sinais/genética , Adolescente , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Transfecção , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
13.
J Neurotrauma ; 38(20): 2831-2840, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34275326

RESUMO

The National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH-NINDS) Traumatic Brain Injury (TBI) Imaging Common Data Elements (CDEs) are standardized definitions for pathological intracranial lesions based on their appearance on neuroimaging studies. The NIH-NINDS TBI Imaging CDEs were designed to be as consistent as possible with the U.S. Food and Drug Administration (FDA) definition of biomarkers as "an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention." However, the FDA qualification process for biomarkers requires proof of reliable biomarker test measurements. We determined the interrater reliability of TBI Imaging CDEs on subacute brain magnetic resonance imaging (MRI) performed on 517 mild TBI patients presenting to 11 U.S. level 1 trauma centers. Three U.S. board-certified neuroradiologists independently evaluated brain MRI performed 2 weeks post-injury for the following CDEs: traumatic axonal injury (TAI), diffuse axonal injury (DAI), and brain contusion. We found very high interrater agreement for brain contusion, with prevalence- and bias-adjusted kappa (PABAK) values for pairs of readers from 0.92 [95% confidence interval, 0.88-0.95] to 0.94 [0.90-0.96]. We found intermediate agreement for TAI and DAI, with PABAK values of 0.74-0.78 [0.70-0.82]. The near-perfect agreement for subacute brain contusion is likely attributable to the high conspicuity and distinctive appearance of these lesions on T1-weighted images. Interrater agreement for TAI and DAI was lower, because signal void in small vascular structures, and artifactual foci of signal void, can be difficult to distinguish from the punctate round or linear areas of slight hemorrhage that are a common hallmark of TAI/DAI on MRI.

14.
Sci Rep ; 11(1): 14210, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244571

RESUMO

Previous research indicates that excessive fear is a critical feature in anxiety disorders; however, recent studies suggest that disgust may also contribute to the etiology and maintenance of some anxiety disorders. It remains unclear if differences exist between these two threat-related emotions in conditioning and generalization. Evaluating different patterns of fear and disgust learning would facilitate a deeper understanding of how anxiety disorders develop. In this study, 32 college students completed threat conditioning tasks, including conditioned stimuli paired with frightening or disgusting images. Fear and disgust were divided into two randomly ordered blocks to examine differences by recording subjective US expectancy ratings and eye movements in the conditioning and generalization process. During conditioning, differing US expectancy ratings (fear vs. disgust) were found only on CS-, which may demonstrated that fear is associated with inferior discrimination learning. During the generalization test, participants exhibited greater US expectancy ratings to fear-related GS1 (generalized stimulus) and GS2 relative to disgust GS1 and GS2. Fear led to longer reaction times than disgust in both phases, and the pupil size and fixation duration for fear stimuli were larger than for disgust stimuli, suggesting that disgust generalization has a steeper gradient than fear generalization. These findings provide preliminary evidence for differences between fear- and disgust-related stimuli in conditioning and generalization, and suggest insights into treatment for anxiety and other fear- or disgust-related disorders.

15.
Front Med (Lausanne) ; 8: 645550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34268318

RESUMO

Background: Our earlier meta-analysis showed that the correlation between psoriasis and hyperuricemia might be region-dependent and that hyperuricemia was more common in patients with psoriasis in Western Europe. However, no further analysis could be conducted owing to the scarcity of data. Objective: Our study aimed to further explore the association between psoriasis and hyperuricemia. Methods: Six databases (PubMed, Embase, the Cochrane Central Register of Controlled Trials, the China National Knowledge Infrastructure database, the Chinese Scientific Journals Full Text Database, and the Wanfang Data Knowledge Service Platform) were searched for studies published between January 1980 and February 2021. Results: The search strategy yielded 291 relevant studies, of which 27 observational studies were included in this analysis. Serum uric acid (SUA) levels (mean difference [MD] 0.99, 95% confidence interval [CI] 0.48-1.49, P = 0.0001) and hyperuricemia frequency (odds ratio [OR] 5.39, 95% CI 1.88-15.40, P = 0.002) were higher in the psoriasis group than in the control group, and the subgroup differences were significant. In addition, SUA levels were significantly higher in patients with moderate to severe psoriasis from European and American countries (MD 0.89, 95% CI 0.18-1.60, P = 0.01) and Southeast Asia (MD 1.79, 95% CI 0.55-3.02, P = 0.004), while no significant differences were found between the Middle East subgroup (MD 0.63, 95% CI -0.33 to 1.59, P = 0.20). Similar results were obtained from the meta-analysis of SUA levels in patients with metabolic syndrome, obesity, or a special type of psoriasis (such as arthritic or erythrodermic psoriasis). Conclusions: Our meta-analysis study provides extended data regarding the correlation between psoriasis and hyperuricemia and the differences in SUA levels between psoriasis patients and controls in Southeast Asia, the Middle East, and European and American countries. Patients with moderate to severe psoriasis in European and American countries and Southeast Asia or those with metabolic syndrome and obesity were more likely to have higher uric acid levels. Systematic Review Registration: PROSPERO, identifier: CRD42014015091.

16.
Signal Transduct Target Ther ; 6(1): 251, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34230452

RESUMO

Circulating tumor DNA (ctDNA) is a potential biomarker of prognosis and therapeutic response. We conducted this study to explore the role of the molecular tumor burden index (mTBI) in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study. We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study (NCT01917279). Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples. The pretreatment mTBI value was correlated with tumor burden (P = 0.025). Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI, and the median overall survival was 40.9 months and 68.4 months, respectively (P = 0.011). Patients with mTBI decrease to less than 0.02% at the first tumor evaluation had longer progression-free survival and overall survival (P < 0.001 and P = 0.007, respectively). The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans (88.5% and 87.5%, respectively). The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort (P < 0.001 and P = 0.036, respectively), as well as in the cohort in which computed tomography scans were defined as representing stable disease (P = 0.027 and P = 0.015, respectively). The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.

17.
Front Immunol ; 12: 670398, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177909

RESUMO

Background: Anti-interleukin (IL)-23 agents are widely used for autoimmune disease treatment; however, the safety and risks of specific symptoms have not been systematically assessed. Objectives: The aim of this study was to summarize the characteristics and mechanisms of occurrence of five immunological and non-immunological adverse events caused by different anti-IL-23 agents. Methods: The Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched for eligible randomized clinical trials published from inception through May 1, 2020. Randomized clinical trials that reported at least one type of adverse event after treatment were included, regardless of sex, age, ethnicity, and diagnosis. Two investigators independently screened and extracted the characteristics of the studies, participants, drugs, and adverse event types. The Cochrane Handbook was used to assess the methodological quality of the included randomized clinical trials. Heterogeneity was assessed using the I2 statistic. Meta-regression was applied to determine the sources of heterogeneity, and subgroup analysis was used to identify the factors contributing to adverse events. Results: Forty-eight studies were included in the meta-analysis, comprising 25,624 patients treated with anti-IL-23 agents. Serious immunological or non-immunological adverse events were rare. Anti-IL-12/23-p40 agents appeared to cause adverse events more easily than anti-IL-23-p19 agents. The incidence of cancer did not appear to be related to anti-IL-23 agent treatment, and long-term medication could lead to mental diseases. The prevention of complications should be carefully monitored when administered for over approximately 40 weeks to avoid further adverse reactions, and the incidence of infection was the highest among general immunological adverse events. Conclusions: The application of anti-IL-23 agents induced a series of immunological and non-immunological adverse events, but these agents tend to be well-tolerated with good safety profiles.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Interleucina-23/antagonistas & inibidores , Humanos
18.
J Neuroinflammation ; 18(1): 131, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34116706

RESUMO

BACKGROUND: Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1ß and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1ß and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aß pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aß.

19.
J Nanobiotechnology ; 19(1): 179, 2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34120620

RESUMO

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is a malignant disease of lymphoid tissue. At present, chemotherapy is still the main method for the treatment of NHL. R-CHOP can significantly improve the survival rate of patients. Unfortunately, DOX is the main cytotoxic drug in R-CHOP and it can lead to adverse reactions. Therefore, it is particularly important to uncover new treatment options for NHL. RESULTS: In this study, a novel anti-tumor nanoparticle complex Nm@MSNs-DOX/SM was designed and constructed in this study. Mesoporous silica nanoparticles (MSNs) loaded with Doxorubicin (DOX) and anti-inflammatory drugs Shanzhiside methylester (SM) were used as the core of nanoparticles. Neutrophil membrane (Nm) can be coated with multiple nanonuclei as a shell. DOX combined with SM can enhance the anti-tumor effect, and induce apoptosis of lymphoma cells and inhibit the expression of inflammatory factors related to tumorigenesis depending on the regulation of Bcl-2 family-mediated mitochondrial pathways, such as TNF-α and IL-1ß. Consequently, the tumor microenvironment (TME) was reshaped, and the anti-tumor effect of DOX was amplified. Besides, Nm has good biocompatibility and can enhance the EPR effect of Nm@MSNs-DOX/SM and increase the effect of active targeting tumors. CONCLUSIONS: This suggests that the Nm-modified drug delivery system Nm@MSNs-DOX/SM is a promising targeted chemotherapy and anti-inflammatory therapy nanocomplex, and may be employed as a specific and efficient anti-Lymphoma therapy.

20.
Psychol Med ; : 1-9, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33947479

RESUMO

BACKGROUND: Definition of disorder subtypes may facilitate precision treatment for posttraumatic stress disorder (PTSD). We aimed to identify PTSD subtypes and evaluate their associations with genetic risk factors, types of stress exposures, comorbidity, and course of PTSD. METHODS: Data came from a prospective study of three U.S. Army Brigade Combat Teams that deployed to Afghanistan in 2012. Soldiers with probable PTSD (PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition ≥31) at three months postdeployment comprised the sample (N = 423) for latent profile analysis using Gaussian mixture modeling and PTSD symptom ratings as indicators. PTSD profiles were compared on polygenic risk scores (derived from external genomewide association study summary statistics), experiences during deployment, comorbidity at three months postdeployment, and persistence of PTSD at nine months postdeployment. RESULTS: Latent profile analysis revealed profiles characterized by prominent intrusions, avoidance, and hyperarousal (threat-reactivity profile; n = 129), anhedonia and negative affect (dysphoric profile; n = 195), and high levels of all PTSD symptoms (high-symptom profile; n = 99). The threat-reactivity profile had the most combat exposure and the least comorbidity. The dysphoric profile had the highest polygenic risk for major depression, and more personal life stress and co-occurring major depression than the threat-reactivity profile. The high-symptom profile had the highest rates of concurrent mental disorders and persistence of PTSD. CONCLUSIONS: Genetic and trauma-related factors likely contribute to PTSD heterogeneity, which can be parsed into subtypes that differ in symptom expression, comorbidity, and course. Future studies should evaluate whether PTSD typology modifies treatment response and should clarify distinctions between the dysphoric profile and depressive disorders.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...