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1.
J Neurol Sci ; 414: 116923, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32447193

RESUMO

OBJECTIVE: To investigate the incidence and spectrum of neuroimaging findings and their prognostic role in hospitalized COVID-19 patients in New York City. METHODS: This is a retrospective cohort study of 3218 COVID-19 confirmed patients admitted to a major healthcare system (three hospitals) in New York City between March 1, 2020 and April 13, 2020. Clinical data were extracted from electronic medical records, and particularly data of all neurological symptoms were extracted from the imaging reports. Four neuroradiologists evaluated all neuroimaging studies for acute neuroimaging findings related to COVID-19. RESULTS: 14.1% of admitted COVID-19 patients had neuroimaging and this accounted for only 5.5% of the total imaging studies. Acute stroke was the most common finding on neuro-imaging, seen in 92.5% of patients with positive neuro-imaging studies, and present in 1.1% of hospitalized COVID-19 patients. Patients with acute large ischemic and hemorrhagic stroke had much higher mortality risk adjusted for age, BMI and hypertension compared to those COVID-19 patients without neuroimaging. (Odds Ratio 6.02 by LR; Hazard Ratio 2.28 by CRR). CONCLUSIONS: Our study demonstrates acute stroke is the most common neuroimaging finding among hospitalized COVID-19 patients. Detection of an acute stroke is a strong prognostic marker of poor outcome. Our study also highlights the fact there is limited use of neuroimaging in these patients due to multiple logistical constraints.

2.
Sci Rep ; 10(1): 7935, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404970

RESUMO

In the era of precision medicine the treatment options for cancer patients and subsequent outcomes are expected to improve. We present a review of patients enrolled in first-in-human Phase1 trials at University of Alabama at Birmingham. Between 1/2015-6/2017, 162 cancer patients (whole cohort, WC) were enrolled on phase1 studies receiving either targeted therapy (TT) or immuno-therapy (IOT). We assessed 90 day mortality (90DM) and time to treatment failure (TTF) to determine the predictors. Of the WC (122 (TT), 40 (IOT)), 90 (56%) received ≥ 2 prior therapies and 38 (24%) ⩾ 5 prior therapies. Overall, Grade 3 or 4 events were observed in 33% (WC) vs 31% (TT) vs 38% (IOT). The 90DM was 9.3% (WC) vs 7.4% (TT) vs 15% (IOT). The median TTF was 4.2 months vs 4.5 m vs 3.6 m. The number of lines of prior therapy and performance status were identified as outcome predictors. Our data reflects the new trend in precision oncology where majority received non-cytotoxic therapeutic interventions. The observation that number of lines of prior therapy and performance status predictive of PFS and 90DM emphasizes the need to consider phase1 trials earlier, preferably upon progression following definitive therapy.

3.
Cell Rep ; 31(4): 107566, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32348763

RESUMO

The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4+ T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1∗0101 transgenic, interferon α/ß receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1∗0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4+ T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1∗0101 transgenic mice with these peptides induces a CD4+ T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4+ T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines.

4.
Breast ; 50: 39-48, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981910

RESUMO

BACKGROUND: Major advances in breast cancer treatment have led to a reducuction in mortality. However, there are still women who are not cured. We hypothesize there is a sub-group of women with treatment-resistant cancers causing early death. METHODS: Between 1975 and 2006, 5392 women with invasive breast cancer underwent surgery at Guy's Hospital, London. Data on patient demographics, tumour characteristics, treatment regimens, local recurrence, secondary metastasis, and death were prospectively recorded. We considered four time periods (1975-1982, 1983-1990, 1991-1998, 1999-2006). Risks and time to event analysis were performed with Cox proportional hazards model and Kaplan-Meier estimation. RESULTS: Unadjusted hazard ratios for developing metastasis and overall mortality relative to the 1975-1982 cohort decreased steadily to 0.23 and 0.63, respectively in 1999-2006. However, metastasis-free interval shortened, with the proportion of women developing metastasis ≤5 years increasing from 73.9% to 83.0%. Furthermore, median post-metastatic survival decreased from 1.49 years to 0.94 years. Applying our risk criteria identified the presence of ±200 patients in each cohort who developed metastasis early and died within a much shorter time frame. CONCLUSIONS: Advances in treatment have decreased the risk of metastasis and improved survival in women with invasive breast cancer over the last 40 years. Despite this, a subpopulation with shorter metastasis-free and post-metastatic survival who are unresponsive to available treatment remains. This may be due to the ATRESS phenomenon (adjuvant therapy-related shortening of survival) secondary to preselection inherent in adjuvant therapy, successful treatment of less malignant tumour cells and treatment-induced resistance in the remaining tumour clones.

5.
Bioinformatics ; 36(3): 964-965, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400197

RESUMO

MOTIVATION: Increasing numbers of large scale single cell RNA-Seq projects are leading to a data explosion, which can only be fully exploited through data integration. A number of methods have been developed to combine diverse datasets by removing technical batch effects, but most are computationally intensive. To overcome the challenge of enormous datasets, we have developed BBKNN, an extremely fast graph-based data integration algorithm. We illustrate the power of BBKNN on large scale mouse atlasing data, and favourably benchmark its run time against a number of competing methods. AVAILABILITY AND IMPLEMENTATION: BBKNN is available at https://github.com/Teichlab/bbknn, along with documentation and multiple example notebooks, and can be installed from pip. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

6.
Spine (Phila Pa 1976) ; 45(1): 18-25, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425431

RESUMO

STUDY DESIGN: Case series OBJECTIVE.: The aim of this study was to assess the patient-reported outcome measures (PROMs) and patient satisfaction of multilevel lumbar total disc arthroplasty (TDA) for symptomatic multilevel degenerative disc disease (MLDDD). SUMMARY OF BACKGROUND DATA: TDA has been shown to be safe and effective for the treatment of symptomatic single level degenerative disc disease. There is minimal PROMs data on the mid- to long-term outcomes of multilevel TDA constructs. METHODS: Prospectively collected PROMs were analyzed from patients receiving multilevel TDA for symptomatic MLDDD. Data were collected preoperatively and postoperatively at 3, 6, and 12 months, then yearly. PROMs included patient satisfaction, Visual Analog Score back and leg, Oswestry Disability Index, and Roland-Morris Disability Questionnaire. RESULTS: One hundred twenty-two patients (77 men, 45 women) who had preoperative and at least 24-month follow-up data were included. The average age was 42 ±â€Š8.2 years (range 21-61) and mean follow-up 7.8 years (range 2-10). The majority received two-level TDA, except two patients (1.6%) who received three-level TDA. The two- to three-level TDA's were at the levels L3-4, L4-5, and L5-S1, whereas most two levels (n = 110, 90.2%) were at L4-5 and L5-S1; the remainder (n = 10, 8.2%) being at L3-4 and L4-5. Implants used were Charité (DePuy Spine, Raynham, MA) in 119 patients (240 levels) and InMotion (DePuy Spine) in 3 patients (6 levels). Improvement in pain and disability scores were both clinically and statistically significant (P < 0.001), and this improvement was sustained in those patients over the course of their follow-up. Ninety-two percent of patients reported good or excellent satisfaction with treatment at final review. CONCLUSION: Multilevel TDA constructs for MLDDD demonstrate favorable and sustained clinical outcomes at mid- to long-term follow-up. LEVEL OF EVIDENCE: 4.

7.
Eur Urol Focus ; 6(2): 339-343, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30392867

RESUMO

BACKGROUND: Botulinum neurotoxin (BotN) is used to treat detrusor overactivity (DO) refractory to medical treatment. Catheterised patients with symptoms of bladder spasm and catheter bypass leakage are challenging to manage and the efficacy of BotN is not established. OBJECTIVE: To review our experience using intravesical BotN to treat refractory bladder pain and catheter bypass leakage in patients with long-term indwelling catheters. DESIGN, SETTING, AND PARTICIPANTS: We carried out a review of data prospectively collected for patients with indwelling urethral or suprapubic catheters receiving BotN for the treatment of bladder spasms and catheter bypass leakage in a UK tertiary centre. An unvalidated structured questionnaire was used to ascertain quality of life (QoL) outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Qualitative data were collected for patient-reported symptoms and QoL. Paired Student t tests were applied for statistical analysis. RESULTS AND LIMITATIONS: Of the 54 catheterised patients who received BotN, 14 (26%) were male and 40 (74%) were female. The mean follow-up was 38mo. Of the patients, 34 (63%) had a neurological aetiology and 94% had experienced failure of medical therapy before BotN administration. The BotN starting dose was 100 or 200U and 17 patients (31%) required dose escalation. All 34 neurogenic and six non-neurogenic patients started on 200U. After treatment, 63% of patients managed their catheter with intermittent drainage and 37% managed on free drainage; 51 patients (94%) reported that their symptoms were controlled and 38% reported being treated for a urinary tract infection following BotN. Patients reported a mean improvement in QoL of 7.7/10 following BotN, while 83% reported a significant reduction in urine leakage (p=0.0001). CONCLUSIONS: Outpatient intravesical BotN is safe and efficacious for patients with long-term catheters suffering from bladder pain and catheter bypass leakage. PATIENT SUMMARY: Outpatient administration of intravesical botulinum toxin is a safe and effective treatment for patients with a long-term indwelling catheter with bothersome urine storage symptoms. Attention should be paid to urine microbiology results before treatment to ensure appropriate prophylactic antibiotic treatment to reduce the incidence of urinary tract infections.

8.
Indoor Air ; 30(2): 213-234, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31709614

RESUMO

Low-cost airborne particle sensors are gaining attention for monitoring human exposure to indoor particulate matter. This study aimed to establish the concentrations at which these commercially available sensors can be expected to report accurate concentrations. We exposed five types of commercial integrated devices and three types of "bare" low-cost particle sensors to a range of concentrations generated by three different sources. We propose definitions of upper and lower bounds of functional range based on the relationship between a given sensor's output and that of a reference instrument during a laboratory experiment. Experiments show that the lower bound can range from approximately 3 to 15 µg/m3 . At greater concentrations, sensor output deviates from linearity at approximately 300-3000 µg/m3 . We also conducted a simulation campaign to analyze the effect of this limitation on functional range on the accuracy of exposure readings given by these devices. We estimate that the upper bound results in minimal inaccuracy in exposure quantification, and the lower bound can result in as much as a 50% error in approximately 10% of US homes.

9.
Clin J Sport Med ; 30(1): e5-e7, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30308551

RESUMO

Chronic persistent lower back pain due to degenerative disc disease (DDD) of the lumbar spine is a common condition in the athletic population, which does not always improve with nonoperative treatment. We present a case report of a professional Australian rugby league player with DDD of the lumbar spine presenting with persistent lower back pain, which was not responding to conventional nonsurgical treatment. He then underwent a surgical total disc replacement of the lumbar spine and was subsequently able to return to playing professional rugby league at his previous level of competition. This is the only known documented case of a professional athlete in any form of contact sport successfully returning to his previous level of function and competition after undergoing a total disc replacement of the lumbar spine.

10.
Cancer Lett ; 472: 50-58, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862408

RESUMO

HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HM1-3 isoform and that HM1-3 is downregulated in >90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.

11.
Can J Public Health ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792845

RESUMO

OBJECTIVE: Policy makers require evidence-based estimates of the economic costs of substance use-attributable lost productivity to set strategies aimed at reducing substance use-related harms. Building on a study by Rehm et al. (2006), we provide estimates of workplace costs using updated methods and data sources. METHODS: We estimated substance use-attributable productivity losses due to premature mortality, long-term disability, and presenteeism/absenteeism in Canada between 2007 and 2014. Lost productivity was estimated using a hybrid prevalence and incidence approach. Substance use prevalence data were drawn from three national self-report surveys. Premature mortality data were from the Canadian Vital Statistics Death Database, and long-term disability and workplace interference data were from the Canadian Community Health Survey. RESULTS: In 2014, the total cost of lost productivity due to substance use was $15.7 billion, or approximately $440 per Canadian, an increase of 8% from 2007. Substances responsible for the greatest economic costs were alcohol (38% of per capita costs), tobacco (37%), opioids (12%), other central nervous system (CNS) depressants (4%), other CNS stimulants (3%), cannabis (2%), cocaine (2%), and finally other psychoactive substances (2%). CONCLUSION: In 2014, alcohol and tobacco represent three quarters of substance use-related lost productivity costs in Canada, followed by opioids. These costs provide a valuable baseline that can be used to assess the impact of future substance use policy, practice, and other interventions, especially important given Canada's opioid crisis and recent cannabis legalization.

12.
Science ; 366(6470): 1247-1251, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806814

RESUMO

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.

13.
J Gambl Stud ; 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31828695

RESUMO

There is little research on the control strategies used by the general public to self-manage gambling habits and avoid harmful consequences. The current study sought to identify the most common self-control strategies of people who gamble regularly, the characteristics of those who use them, and assess the effectiveness of limit-setting strategies in reducing gambling-related harm. We recruited a large sample (N = 10,054) of Canadian adults who reported gambling activity in the past 12 months. Participants completed a survey that assessed gambling habits, use of control strategies including quantitative limit setting, and gambling related harm. The most common control strategies were setting predetermined spending limits, tracking money spent, and limiting alcohol consumption. The number of self-control strategies used by gamblers was positively associated with gambling involvement, annual income, problem gambling severity and playing electronic gaming machines. Approximately 45% of respondents failed to adhere to self-determined quantitative limits for spending, frequency, and time spent gambling. People who stayed within their gambling limits were less likely to report harm even after controlling for other risk factors. However, the effectiveness of remaining within one's personal spending limit decreased for those whose limits exceed $200CAN monthly. The findings support public health interventions that promote lower-risk gambling guidelines aimed at helping gamblers stay within spending, frequency and duration limits.

14.
Nature ; 574(7778): 365-371, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597962

RESUMO

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.

15.
Science ; 365(6460): 1461-1466, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31604275

RESUMO

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.

16.
Syst Rev ; 8(1): 191, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31370881

RESUMO

BACKGROUND: Experiencing a lower limb amputation (LLA) or spinal cord injury (SCI) is a life-changing event, affecting physical and systemic function as well as having psychological and social impacts. However, the severity of the physical impairment and/or motor disability demonstrates a poor relationship with patient-reported quality of life, suggesting that other factors determine such outcomes. As such, holistic health-related quality of life (QoL) assessment is an important tool to monitor long-term outcomes. While there are some studies that have assessed the influence of variables such as age at time of injury occurrence and time since injury on changes in QoL, there are no systematic reviews which synthesise this evidence. METHODS/DESIGN: All follow-up study designs will be included, where data from multiple time points are presented. Searches will target both SCI and LLA populations where a validated measure of QoL has been used: Medical Outcome Study Short-Form 36/12 or the World Health Organization Quality of Life instruments 100 and BREF. Studies must include adult participants (≥ 18 years at time of injury) and detail time since injury event and patient age. The primary objective is to establish the effects of participant age and time since injury on QoL scores. Secondary objectives include determining between-group effects (i.e. LLA vs. SCI). We will search PubMed, Embase and Web of Science databases, supplemented by hand-searching references within existing review articles and experimental studies. Reviewer pairs will conduct screening and quality assessment of included papers. Results will be stratified by impairment, QoL tool, age/time since injury and additional variables such as sex, race, comorbidity or disease aetiology, as appropriate. If sufficient high-quality data exist, a meta-analysis will be conducted. DISCUSSION: The results of this systematic review will summarise evidence of how QoL changes across the life course, relative to both patient age and time since injury, for both LLA and SCI populations. By enabling a direct comparison of different chronic conditions, disability-specific differences in QoL changes over the life course can be identified. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018096633 .

17.
J Orthop Trauma ; 33(11): 564-568, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356448

RESUMO

OBJECTIVE: To determine whether a position screw will maintain the interfragmentary compression force obtained by a reduction clamp across an anatomically reduced cortical bone fracture and determine whether this compressive force is equivalent to that generated by a lag screw (LS). METHODS: Oblique fractures were created in 6 composite cortical bone models. Interfragmentary compression was measured using force sensors within the fracture after reduction with a clamp. A position screw was then placed perpendicular to the fracture, and force measurements were repeated with both the clamp and the screw. Finally, the clamp was removed, and force measurements were taken with the screw only to measure maintenance of initial compression. After these measurements, the screw was removed, and the near fragment was overdrilled to allow LS placement by technique. Compression force measurements were repeated for clamp only, clamp + screw, and screw only. RESULTS: The mean force of clamp alone across all 12 trials was 139.77 N. Application of an LS increased the compression across the fracture (P = 0.01) which was unchanged when the clamp was removed. The position screw had the opposite effect, reducing compression, and the removal of the clamp further reduced the compression (P = 0.013). CONCLUSIONS: A reduction clamp will initially compress a fracture to an average of 139 N. An LS will significantly increase this interfragmentary compression. A position screw will not maintain the compression created by the clamp and in fact will significantly decrease interfragmentary compression.

18.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269646

RESUMO

The mitochondrial DNA (mtDNA) sequences of two commonly used human cell lines, HepaRG and SJCRH30, were determined. HepaRG originates from a liver tumor obtained from a patient with hepatocarcinoma and hepatitis C while SJCRH30 originates from a rhabdomyosarcoma patient tumor. In comparison to the revised Cambridge Reference Sequence, HepaRG and SJCRH30 mtDNA each contain 14 nucleotide variations. In addition to an insertion of a cytosine at position 315 (315insC), the mtDNA sequences from both cell types share six common polymorphisms. Heteroplasmic variants were identified in both cell types and included the identification of the 315insC mtDNA variant at 42 and 75% heteroplasmy in HepaRG and SJCRH30, respectively. Additionally, a novel heteroplasmic G13633A substitution in the HepaRG ND5 gene was detected at 33%. Previously reported cancer-associated mtDNA variants T195C and T16519C were identified in SJCRH30, both at homoplasmy (100%), while HepaRG mtDNA harbors a known prostate cancer-associated T6253C substitution at near homoplasmy, 95%. Based on our sequencing analysis, HepaRG mtDNA is predicted to lie within haplogroup branch H15a1 while SJCRH30 mtDNA is predicted to localize to H27c. The catalog of polymorphisms and heteroplasmy reported here should prove useful for future investigations of mtDNA maintenance in HepaRG and SJCRH30 cell lines.


Assuntos
Carcinoma Hepatocelular/genética , DNA Mitocondrial/genética , Neoplasias Hepáticas/genética , Polimorfismo Genético , Rabdomiossarcoma/genética , Carcinoma Hepatocelular/complicações , Linhagem Celular Tumoral , Hepatite C/complicações , Hepatite C/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/complicações , Mitocôndrias/genética , Análise de Sequência de DNA
19.
Sci Rep ; 9(1): 9857, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285451

RESUMO

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that represents a major threat to global health. ZIKV infections in adults are generally asymptomatic or present with mild symptoms. However, recent outbreaks of ZIKV have revealed that it can cause Congenital Zika Syndrome in neonates and Guillain-Barré syndrome in adults. Currently, no ZIKV-specific vaccines or antiviral treatments are available. In this study, we tested the efficacy of convalescent plasma IgG hyperimmune product (ZIKV-IG) isolated from individuals with high neutralizing anti-ZIKV titers as a therapeutic candidate against ZIKV infection using a model of ZIKV infection in Ifnar1-/- mice. ZIKV-IG successfully protected mice from lethal ZIKV challenge. In particular, ZIKV-IG treatment at 24 hours after lethal ZIKV infection improved survival by reducing weight loss and tissue viral burden and improving clinical score. Additionally, ZIKV-IG eliminated ZIKV-induced tissue damage and inflammation in the brain and liver. These results indicate that ZIKV-IG is efficacious against ZIKV, suggesting this human polyclonal antibody is a viable candidate for further development as a treatment against human ZIKV infection.

20.
J Exp Med ; 216(8): 1828-1842, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31196981

RESUMO

Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2-inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals.

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