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1.
Br J Haematol ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131896

RESUMO

There is limited understanding of the impact of frailty on clinical outcomes in patients with myelofibrosis (MF). In this retrospective cohort study on 439 chronic phase MF patients [mean age: 68·7 ± 12 years; median follow-up: 3·4 years (IQR 0·4-8·6)] from 2004 till 2018, we used a 35-variable frailty index (FI) to categorise patient's frailty status as fit (FI < 0·2, reference), prefrail (FI 0·2-0·29) or frail (FI ≥ 0·3). The association of frailty with overall survival (OS) and cumulative JAK inhibitor (JAKi) therapy failure was measured using hazard ratio (HR, 95% CI). In multivariable analysis, prefrail (HR 1·7, 1·1-2·5) and frail patients (HR 2·9, 1·6-5·5), those with higher DIPSS score (HR 2·5, 1·6-3·9) and transfusion dependency (HR 1·9, 1·3-2·9) had shorter OS. In a subset analysis of patients on JAKi treatment (n = 222), frail patients (HR 2·5, 1·1-5·7), patients with higher DIPSS score (HR 1·7, 1·0-3·1) and transfusion dependence (HR 1·7, 1·1-2·7) had higher cumulative incidence of JAKi failure. Age, comorbidities, ECOG performance status, and MPN driver mutations did not impact outcomes. Thus, higher frailty scores are associated with worse OS and increased JAKi failure in MF, and is a superior indicator of fitness in comparison to age, comorbidities, and performance status.

2.
Clin Infect Dis ; 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34143881

RESUMO

BACKGROUND: Uncomplicated urinary tract infection (uUTI) is predominantly caused by Escherichia coli, which has increasing antimicrobial resistance (AMR) at the US-community level. As uUTI is often treated empirically, assessing AMR is challenging and there are limited contemporary data characterizing period prevalence in the US. METHODS: This was a retrospective study of AMR using Becton, Dickinson and Company Insights Research Database (Franklin Lakes, NJ) data collected 2011-2019. Thirty-day, non-duplicate Escherichia coli urine isolates from US female outpatients (aged ≥12 years) were included. Isolates were evaluated for not-susceptibility (intermediate/resistant) to trimethoprim-sulfamethoxazole, fluoroquinolones, or nitrofurantoin, and assessed for extended-spectrum ß-lactamase production (ESBL+) and for ≥2 or ≥3 drug-resistance phenotypes. Generalized estimating equations were used to model AMR trends over time and by US census region. RESULTS: Among 1,513,882 Escherichia coli isolates, the overall prevalence of isolates not-susceptible to trimethoprim-sulfamethoxazole, fluoroquinolones, and nitrofurantoin was 25.4%, 21.1%, and 3.8%, respectively. Among the isolates, 6.4% were ESBL+, 14.4% had ≥2 drug-resistance phenotypes, and 3.8% had ≥3. Modelling demonstrated a relative average yearly increase of 7.7% (95% confidence interval [CI], 7.2-8.2%) for ESBL+ isolates and 2.7% (95% CI, 2.2-3.2%) for ≥3 drug-phenotypes (both p<0.0001). Modelling also demonstrated significant variation in AMR prevalence between US census regions (p<0.001). CONCLUSIONS: Period prevalence of AMR among US outpatient urine-isolated Escherichia coli was high, and for multi-drug-resistance phenotypes increased during the study period with significant variation between census regions. Knowledge of regional AMR rates helps inform empiric treatment of community-onset uUTI and highlights the AMR burden to physicians.

3.
Braz J Microbiol ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34128211

RESUMO

Canine adenoviruses (CAVs) are of two types: canine adenovirus type 1 (CAV-1), which causes infectious canine hepatitis, and canine adenovirus type 2 (CAV-2), which is mainly associated with the respiratory type of disease in dogs. Due to the widespread use of modified live vaccines to control canine adenoviral infections and subsequently reduced disease incidence, CAVs are often neglected by clinicians. Although a number of studies are available about CAV-1 prevalence in India, only meagre information is available about CAV-2. This study reports the CAV-2 infection in a vaccinated dog with neurological and respiratory symptoms which was found negative for other canine pathogens like canine distemper virus and canine parvovirus. The virus was successfully isolated from rectal swab in MDCK cells and characterized by immunofluorescence assay and virus neutralization test. On phylogenetic analysis of partial E3 region, the Indian CAV-2 grouped in a separate clade different from established subgroups. An insertion of "G" nucleotide was reported at nucleotide (nt.) position 1077 in the E3 gene of Indian CAV-2 isolates which led to a frameshift in the coding region of E3 gene thereby imparting additional eleven amino acids to its C-terminal end in comparison to isolates from other parts of the world. This may have an implication on the functional role of E3 protein inside the cell. This study reinforces the unique signature insertion in the E3 gene of Indian CAV-2 and is the second study in the world to report the association of CAV-2 with neurological disease in dogs.

5.
Annu Rev Biomed Eng ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33974812

RESUMO

Liver disease is an important clinical problem, impacting 600 million people worldwide. It is the 11th-leading cause of death in the world. Despite constant improvement in treatment and diagnostics, the aging population and accumulated risk factors led to increased morbidity due to nonalcoholic fatty liver disease and steatohepatitis. Liver transplantation, first established in the 1960s, is the second-most-common solid organ transplantation and is the gold standard for the treatment of liver failure. However, less than 10% of the global need for liver transplantation is met at the current rates of transplantation due to the paucity of available organs. Cell- and tissue-based therapies present an alternative to organ transplantation. This review surveys the approaches and tools that have been developed, discusses the distinctive challenges that exist for cell- and tissue-based therapies, and examines the future directions of regenerative therapies for the treatment of liver disease. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

6.
J Matern Fetal Neonatal Med ; : 1-7, 2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-33998394

RESUMO

PURPOSE: The purpose of this study was to analyze the clinical characteristics and outcomes of low birthweight (LBW) infants with congenital diaphragmatic hernia (CDH) compared to normal birthweight (NBW) infants with CDH. We hypothesized that LBW was associated with increased mortality, decreased extracorporeal life support (ECLS) utilization, and increased pulmonary morbidity in CDH patients. METHODS: Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as <2.5 kg. Clinical characteristics and outcomes for LBW patients were compared to normal birthweight (NBW) patients using univariate and multivariable analyses. RESULTS: Of 5,586 patients, 1,157 (21%) were LBW. LBW infants had more congenital anomalies and larger diaphragmatic defects than NBW infants. ECLS utilization was decreased, and overall mortality was increased among LBW infants compared to NBW infants. A 1 kg increase in birthweight was associated with 34% higher odds of survival after repair (adjusted Odds Ratio 1.34, 95% CI 1.03-1.76; p = .03). LBW infants had longer durations of mechanical ventilation and were more likely to require supplemental oxygen at 30 days and at the time of discharge. CONCLUSION: LBW is a risk factor for mortality and pulmonary morbidity in CDH. Prolonged oxygen requirement and increased length of stay are important considerations when managing this population.

7.
Psychiatr Clin North Am ; 44(2): 249-261, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34049647

RESUMO

Multiple-choice tests are the most used method of assessment in medical education. However, there is limited literature in medical education and psychiatry to inform the best practices in writing good-quality multiple-choice questions. Moreover, few physicians and psychiatrists have received training and have experience in writing them. This article highlights the strategies in writing high-quality multiple-choice items and discusses some common flaws that can impact validity and reliability of the assessment examinations.

8.
Neonatology ; 118(2): 147-154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33849011

RESUMO

INTRODUCTION: Pulmonary hypertension (PH) is the major pathophysiologic consequence of congenital diaphragmatic hernia (CDH). We aimed to evaluate the association between early CDH-associated PH (CDH-PH) and inpatient outcomes. METHODS: The CDH Study Group registry was queried for infants born 2015-2019 with echocardiograms before 48h of life. PH was categorized using echocardiographic findings: none, mild (right ventricular systolic pressure <2/3 systemic), moderate (between 2/3 systemic and systemic), or severe (supra-systemic). Univariate and multivariate analyses were performed. Adjusted Poisson regression was used to assess the primary composite outcome of mortality or oxygen support at 30 days. RESULTS: Of 1,472 patients, 86.5% had CDH-PH: 13.9% mild (n = 193), 44.4% moderate (n = 631), and 33.2% severe (n = 468). On adjusted analysis, the primary outcome of mortality or oxygen support at 30 days occurred more frequently in infants with moderate (incidence rate ratio [IRR] 1.8, 95% confidence interval [CI], 1.2-2.6) and severe CDH-PH (IRR 2.0, 95% CI, 1.3-2.9). Extracorporeal life support (ECLS) utilization was associated only with severe CDH-PH after adjustment (IRR 1.8, 95% CI, 1.0-3.3). DISCUSSION/CONCLUSION: Early, postnatal CDH-PH is independently associated with increased risk for mortality or oxygen support at 30 days and utilization of ECLS. Early echocardiogram is a valuable prognostic tool for early, inpatient outcomes in neonates with CDH.

9.
J Surg Res ; 264: 236-241, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33838408

RESUMO

BACKGROUND: Although physiologic differences exist between younger and older children, pediatric trauma analyses are weighted toward older patients. Trauma-induced coagulopathy, determined by rapid thrombelastography (rTEG), is a predictor of outcome in trauma patients, but the significance of rTEG values among very young trauma patients remains unknown. Our objective was to identify the prehospital or physiologic factors, including rTEG values, that were associated with mortality in trauma patients younger than 5 y old. MATERIALS AND METHODS: Patients younger than 5 y old that met the highest-level trauma activation criteria at an academic children's hospital from 2010-2016 were included. Data regarding demographics, pre-hospital management, laboratory values, injury severity, and outcome were queried. Univariate and multivariate analyses were performed comparing survivors and non-survivors. RESULTS: A total of 356 patients were included. 60% were male, and the median age was 3 y (IQR 1-4). Overall mortality was 13% (n = 45); brain injury (91%) and hemorrhage (9%) were the causes of death. Compared to survivors, rTEG values in nonsurvivors showed longer activated clotting time and slower speed of clot formation. Clot strength was also decreased in nonsurvivors. On stepwise regression modeling, rTEG values were not significant predictors of mortality. Admission base deficit, arrival temperature, and head injury severity were identified as independent predictors of mortality. CONCLUSIONS: While rTEG identified coagulopathy in trauma patients < 5 y old, it was not an independent predictor of mortality. Our findings suggest that trauma providers should pay close attention to admission base deficit, arrival temperature, and head injury severity when managing the youngest trauma patients.

10.
Am J Infect Control ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33891989

RESUMO

BACKGROUND: The diagnosis-related group (DRG) is a payment system introduced to standardize healthcare costs. However, reimbursement for treatment of infections does not always cover costs. METHODS: We used 2015-2018 data from 92 US hospitals in the Becton Dickinson Insights Research Database to compare the financial burden of hospital admissions within non-infection DRGs for patients with a bacterial infection (INF+) versus those without an infection (INF-). Included patients were adults with a hospital length of stay (LOS) ≥3 days and evidence of infection. Multi-variable adjusted analyses via generalized linear mixed models were used to evaluate the impact of an infection on outcomes. RESULTS: We analyzed data from 133,423 INF+ admissions and 170,531 INF- admissions. Infections were associated with an approximately two-fold increase in model-estimated LOS (9.2 vs 4.8 d; P < .001) and intensive care unit LOS (5.1 vs 2.8 d; P < .001). The average additional hospital cost for INF+ versus INF- admissions was $10,326 per admission (P < .001) and the average loss after reimbursement was $1,067 (P = .006). Only private insurance payers had a positive margin. CONCLUSIONS: Current reimbursement options for infections result in significant hospital financial burden. Reimbursement models should be reconsidered to enable adoption of costlier diagnostics and antimicrobials.

11.
Indian J Tuberc ; 68(2): 215-220, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33845955

RESUMO

INTRODUCTION: The variable course of illness in patients of Tubercular lymphadenitis remains a therapeutic challenge to treating physicians in a significant proportion of patients. This study was aimed to explore the possible determinants which could predict the outcome of this subgroup of patients. METHODOLOGY: This was a prospective cohort study where 94 patients of TB lymphadenitis were enrolled who could be followed up till the end of treatment. They were evaluated in the beginning and monitored till the end of treatment keeping into account the clinical behaviour of lymph nodes during the course of Anti tubercular chemotherapy. RESULTS: Out of 94 patients, 60 had their lymph nodes resolved at the end of prescribed treatment duration wheras 34 were classified as partial responders. Another 26 amongst them had their nodes resolved by an extension of continuation phase by 3-6 months. Presence of bilateral and multiple lymph nodes, necrosis on Fine needle aspiration at initial diagnosis and occurrence of Paradoxical upgrading reaction were associated with the partial resolution of lymph nodes at the end of stipulated ATT duration. CONCLUSION: Treatment duration should be individualized by the treating physicians. Certain parameters mentioned above can be taken as warning signals of patients ending up as partial responders and hence the need of a prolonged extension phase.

13.
Sci Prog ; 104(2): 368504211011876, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33908291

RESUMO

This study evaluated an antibiotic stewardship program (ASP) intervention aimed at reducing inpatient fluoroquinolone (FQ) use and examined its impact on ciprofloxacin susceptibilities of gram-negative bacteria in a large 611-bed community hospital. A two-step ASP intervention was implemented: an electronic medical record algorithm that prompted physicians to re-evaluate FQ use shortly after admission and changed institutional UTI/pneumonia guidelines that recommended options alternate to FQs for first-line empiric antibiotic therapy in 2010 and 2011 respectively. Between 2007 and 2017 FQ use and ciprofloxacin susceptibilities of all non-duplicate cultured isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa obtained ≥72 h after admission were reviewed. Ambulatory care isolates served as a comparison group. FQ utilization rates and relationships to ciprofloxacin susceptibility were evaluated using interrupted time series models. Over the 11-year period, FQ use decreased from 110.0 (2007) to 26.2 (2017) days of therapy/1000 days at risk (p < 0.001). Compared to pre-intervention, the estimated (post-intervention) reduction in FQ utilization was 28.4 (95% CI: 10.9-46) days of therapy/1000 days at risk. Reduced FQ utilization was correlated with increase susceptibilities to ciprofloxacin of hospital onset isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis (p < 0.02), and Pseudomonas aeruginosa (p = 0.07). No significant susceptibility change was observed in the ambulatory care isolates. Persuasive interventions by an ASP successfully modified physicians' inpatient empiric antibiotic use, produced a sustained reduction in FQ utilization rates and increased ciprofloxacin susceptibility to four commonly encountered gram-negative bacteria in a community hospital.

14.
JAMA Netw Open ; 4(4): e216556, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33830226

RESUMO

Importance: Mortality is an important measure of the severity of a pandemic. This study aimed to understand how mortality by age of hospitalized patients who were tested for SARS-CoV-2 has changed over time. Objective: To evaluate trends in in-hospital mortality among patients who tested positive for SARS-CoV-2. Design, Setting, and Participants: This retrospective cohort study included patients who were hospitalized for at least 1 day at 1 of 209 US acute care hospitals of variable size, in urban and rural areas, between March 1 and November 21, 2020. Eligible patients had a SARS-CoV-2 polymerase chain reaction (PCR) or antigen test within 7 days of admission or during hospitalization, and a record of discharge or in-hospital death. Exposure: SARS-CoV-2 positivity. Main Outcomes and Measures: SARS-CoV-2 infection was defined as a positive SARS-CoV-2 PCR or antigen test within 7 days before admission or during hospitalization. Mortality was extracted from electronically available data. Results: Among 503 409 admitted patients, 42 604 (8.5%) had SARS-CoV-2-positive tests. Of those with SARS-CoV-2-positive tests, 21 592 (50.7%) were male patients. Hospital admissions among patients with SARS-CoV-2-positive tests were highest in the group aged 65 years or older (19 929 [46.8%]), followed by those aged 50 to 64 years (11 602 [27.2%]) and 18 to 49 years (10 619 [24.9%]). Hospital admissions among patients 18 to 49 years of age increased from 1099 of 5319 (20.7%) in April to 1266 of 4184 (30.3%) in June and 2156 of 7280 (29.6%) in July, briefly exceeding those in the group 50 to 64 years of age (June: 1194 of 4184 [28.5%]; 2039 of 7280 [28.0%]). Patients with SARS-CoV-2-positive tests had higher in-hospital mortality than patients with SARS-CoV-2-negative tests (4705 [11.0%] vs 11 707 of 460 805 [2.5%]; P < .001). In-hospital mortality rates increased with increasing age for both patients with SARS-CoV-2-negative tests and SARS-CoV-2-positive tests. In patients with SARS-CoV-2-negative tests, mortality increased from 45 of 11 255 (0.4%) in those younger than 18 years to 4812 of 107 394 (4.5%) in those older than 75 years. In patients with SARS-CoV-2-positive tests, mortality increased from 1 of 454 (0.2%) of those younger than 18 years to 2149 of 10 287 (20.9%) in those older than 75 years. In-hospital mortality rates among patients with SARS-CoV-2-negative tests were similar for male and female patients (6273 of 209 086 [3.0%] vs 5538 of 251 719 [2.2%]) but higher mortality was observed among male patients with SARS-CoV-2-positive tests (2700 of 21 592 [12.5%]) compared with female patients with SARS-CoV-2-positive tests (2016 of 21 012 [9.60%]). Overall, in-hospital mortality increased from March to April (63 of 597 [10.6%] to 1047 of 5319 [19.7%]), then decreased significantly to November (499 of 5350 [9.3%]; P = .04), with significant decreases in the oldest age groups (50-64 years: 197 of 1542 [12.8%] to 73 of 1341 [5.4%]; P = .02; 65-75 years: 269 of 1182 [22.8%] to 137 of 1332 [10.3%]; P = .006; >75 years: 535 of 1479 [36.2%] to 262 of 1505 [17.4%]; P = .03). Conclusions and Relevance: This nationally representative study supported the findings of smaller, regional studies and found that in-hospital mortality declined across all age groups during the period evaluated. Reductions were unlikely because of a higher proportion of younger patients with lower in-hospital mortality in the later period.


Assuntos
COVID-19/mortalidade , Mortalidade Hospitalar/tendências , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
15.
World Neurosurg ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819705

RESUMO

BACKGROUND: Venous stenting (VS) for venous sinus stenosis in the setting of idiopathic intracranial hypertension has been increasing in acceptance by neurointerventionalists. Stent-adjacent stenosis (SAS) and in-stent stenosis leading to symptom recurrence and the need for retreatment are known delayed complications. However, the effect of the dual antiplatelet therapy (DAPT) duration on these complications has remained poorly characterized. METHODS: An extensive literature search was performed to identify reports of VS for patients with idiopathic intracranial hypertension from 2000 to 2020. The primary outcome was the occurrence of SAS. The secondary outcomes included the occurrence of composite stenosis (in-stent stenosis and SAS) and stent survival, defined as the need for retreatment or other surgical management. Generalized linear mixed models were used to explore the effects of DAPT duration (3 vs ≥6 months) on the primary and secondary outcomes. RESULTS: A total of 325 patients met the inclusion criteria and were included in our analysis. SAS occurred in 9% (95% confidence interval, 6%-15%) of the patients, and stent survival was 90% (95% confidence interval, 84%-93%) in the cohort. With every 1-mm Hg increase in the venous pressure gradient, an 8% decrease was found in the odds of stent survival (P = 0.043). The meta-regression revealed no association between the DAPT duration and the primary outcome or the odds of composite stenosis and stent survival. CONCLUSIONS: We found no differences between 3 and ≥6 months of DAPT in terms of the risk of stent stenosis or stent survival. However, patients with a higher venous pressure gradient before VS had a greater risk of stent failure.

16.
Nat Commun ; 12(1): 2455, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911081

RESUMO

The mutational mechanisms underlying recurrent deletions in clonal hematopoiesis are not entirely clear. In the current study we inspect the genomic regions around recurrent deletions in myeloid malignancies, and identify microhomology-based signatures in CALR, ASXL1 and SRSF2 loci. We demonstrate that these deletions are the result of double stand break repair by a PARP1 dependent microhomology-mediated end joining (MMEJ) pathway. Importantly, we provide evidence that these recurrent deletions originate in pre-leukemic stem cells. While DNA polymerase theta (POLQ) is considered a key component in MMEJ repair, we provide evidence that pre-leukemic MMEJ (preL-MMEJ) deletions can be generated in POLQ knockout cells. In contrast, aphidicolin (an inhibitor of replicative polymerases and replication) treatment resulted in a significant reduction in preL-MMEJ. Altogether, our data indicate an association between POLQ independent MMEJ and clonal hematopoiesis and elucidate mutational mechanisms involved in the very first steps of leukemia evolution.


Assuntos
Hematopoiese Clonal/genética , Reparo do DNA por Junção de Extremidades/genética , DNA Polimerase Dirigida por DNA/genética , Leucemia Mieloide/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Afidicolina/farmacologia , Calreticulina/genética , Quebras de DNA de Cadeia Dupla , DNA Polimerase Dirigida por DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Células Progenitoras Mieloides , Proteínas Repressoras/genética , Deleção de Sequência/genética , Fatores de Processamento de Serina-Arginina/genética
18.
Transplant Cell Ther ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33798769

RESUMO

Despite the curative potential of allogeneic hematopoietic cell transplantation (HCT) for myelofibrosis (MF), a significant number of patients with MF do not undergo HCT. Factors influencing treatment preferences in these patients have not been well studied. This study was conducted to identify patient-, disease-, and donor-related factors influencing the decision regarding HCT in patients with MF. A secondary objective was to compare survival between patients who elected upfront HCT and those who opted for nontransplantation therapy. We conducted a retrospective chart review amongst patients meeting criteria for transplant indication, evaluating clinical characteristics, treatment preferences, and outcomes. Of the 183 study eligible patients age <70 years, 129 (70%) developed an HCT indication. Age >60 years was significantly associated with higher rates of HLA-typing refusal (13 of 72 versus 1 of 44; P = .02). Caucasian ethnicity was significantly associated with an increased rate of identifying well-matched donors compared with non-Caucasian ethnicity (75% versus 48%; P = .02). Of the 69 patients with well-matched donors, 34 (49%) preferred to not pursue upfront HCT despite an indication for transplantation. Patient preference for nontransplantation therapies was the most common reason for declining HCT. We did not find any difference in survival between patients pursuing upfront HCT and those opting for nontransplantation therapies, although more patients in the HCT arm were in remission at the last follow-up. Patients of Caucasian ethnicity were significantly more likely than non-Caucasian patients to identify a well-matched donor. Despite availability of a well-matched donor, a significant proportion of MF patients with an indication for transplantation do not pursue HCT. Patient age, donor type, and patient preference play major roles in the selection of upfront HCT. Although a survival difference was not observed between upfront HCT versus non-transplant therapy, more patients in the HCT arm were in remission at the last follow-up.

19.
Clin Cancer Res ; 27(11): 3178-3189, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33731366

RESUMO

PURPOSE: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. EXPERIMENTAL DESIGN: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1-6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297). RESULTS: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. CONCLUSIONS: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

20.
New Phytol ; 230(6): 2459-2473, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33759450

RESUMO

Forward and reverse genetics using the model legumes Lotus japonicus and Medicago truncatula have been instrumental in identifying the essential genes governing legume-rhizobia symbiosis. However, little information is known about the effects of intraspecific variation on symbiotic signalling. Here, we use quantitative trait locus sequencing (QTL-seq) to investigate the genetic basis of the differentiated phenotypic responses shown by the Lotus accessions Gifu and MG20 to inoculation with the Mesorhizobium loti exoU mutant that produces truncated exopolysaccharides. We identified through genetic complementation the Pxy gene as a component of this differential exoU response. Lotus Pxy encodes a leucine-rich repeat receptor-like kinase similar to Arabidopsis thaliana PXY, which regulates stem vascular development. We show that Lotus pxy insertion mutants displayed defects in root and stem vascular organisation, as well as lateral root and nodule formation. Our work links Pxy to de novo organogenesis in the root, highlights the genetic overlap between regulation of lateral root and nodule formation, and demonstrates that natural variation in Pxy affects nodulation signalling.


Assuntos
Lotus , Mesorhizobium , Regulação da Expressão Gênica de Plantas , Lotus/genética , Lotus/metabolismo , Mesorhizobium/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Nódulos Radiculares de Plantas/genética , Nódulos Radiculares de Plantas/metabolismo , Simbiose/genética
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