Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting ...histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
The growth of malignant cells is not only driven by cell-intrinsic factors, but also by the surrounding stroma. Monocytes/Macrophages play an important role in the onset and progression of solid ...cancers. However, little is known about their role in the development of acute myeloid leukemia, a malignant disease characterized by an aberrant development of the myeloid compartment of the hematopoietic system. It is also unclear which factors are responsible for changing the status of macrophage polarization, thus supporting the growth of malignant cells instead of inhibiting it. We report herein that acute myeloid leukemia leads to the invasion of acute myeloid leukemia-associated macrophages into the bone marrow and spleen of leukemic patients and mice. In different leukemic mouse models, these macrophages support the in vitro expansion of acute myeloid leukemia cell lines better than macrophages from non-leukemic mice. The grade of macrophage infiltration correlates in vivo with the survival of the mice. We found that the transcriptional repressor Growth factor independence 1 is crucial in the process of macrophage polarization, since its absence impedes macrophage polarization towards a leukemia supporting state and favors an anti-tumor state both in vitro and in vivo These results not only suggest that acute myeloid leukemia-associated macrophages play an important role in the progression of acute myeloid leukemia, but also implicate Growth factor independence 1 as a pivotal factor in macrophage polarization. These data may provide new insights and opportunities for novel therapies for acute myeloid leukemia.
Purpose: To assess the comparative effectiveness, efficacy, and tolerability of lamotrigine (LTG) and sustained‐release carbamazepine (CBZ) in the treatment of newly diagnosed epilepsy in the ...elderly.
Methods: Patients aged 65 years or older, who had experienced at least two unprovoked partial and/or generalized tonic–clonic seizures, were randomized to receive LTG (n = 93) or CBZ (n = 92) according to a multicenter double‐blind, parallel‐group design. Trial duration was 40 weeks and included a 4‐week dose escalation followed by a maintenance phase during which dosages could be adjusted according to response. Initial, maintenance and maximum dosages were 25 mg, 100 mg, and 500 mg per day for LTG, and 100 mg, 400 mg, and 2,000 mg per day for CBZ, respectively. The primary end point was retention in the trial.
Results: In the LTG group, 68 patients (73%) completed the 40‐week study period compared with 61 (67%) in the CBZ group, a nonsignificant difference. Time to withdrawal from any cause did not differ between groups (p = 0.34). The number of subjects who completed the 40‐week period and were seizure free in the last 20 weeks was 48 (52%) in the LTG group and 52 (57%) in the CBZ group. Adverse events leading to withdrawal occurred in 13 (14%) subjects in the LTG group and 23 (25%) subjects in the CBZ group.
Conclusion: LTG and CBZ showed comparable effectiveness, with a trend for higher seizure‐free rates for CBZ and better tolerability for LTG. Differences in outcome compared with previous trials may be related to different dosing rates and use of a sustained‐release formulation for CBZ.
Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle-like cells. Previous descriptions of clinical characteristics of ...subjects with lymphangioleiomyomatosis have been based on a limited number of patients.
To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis-related forms.
Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report.
All 230 subjects were women, aged 18 to 76 yr (mean +/- SE, 44.5 +/- 0.65 yr). The average age at onset of symptoms was 38.9 +/- 0.73 yr and at diagnosis was 41.0 +/- 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis-related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form.
The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.
To develop prediction models using machine-learning (ML) algorithms for 90-day and one-year mortality prediction in femoral neck fracture (FNF) patients aged 50 years or older based on the Hip ...fracture Evaluation with Alternatives of Total Hip arthroplasty versus Hemiarthroplasty (HEALTH) and Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trials. This study included 2,388 patients from the HEALTH and FAITH trials, with 90-day and one-year mortality proportions of 3.0% (71/2,388) and 6.4% (153/2,388), respectively. The mean age was 75.9 years (SD 10.8) and 65.9% of patients (1,574/2,388) were female. The algorithms included patient and injury characteristics. Six algorithms were developed, internally validated and evaluated across discrimination (c-statistic; discriminative ability between those with risk of mortality and those without), calibration (observed outcome compared to the predicted probability), and the Brier score (composite of discrimination and calibration). The developed algorithms distinguished between patients at high and low risk for 90-day and one-year mortality. The penalized logistic regression algorithm had the best performance metrics for both 90-day (c-statistic 0.80, calibration slope 0.95, calibration intercept -0.06, and Brier score 0.039) and one-year (c-statistic 0.76, calibration slope 0.86, calibration intercept -0.20, and Brier score 0.074) mortality prediction in the hold-out set. Using high-quality data, the ML-based prediction models accurately predicted 90-day and one-year mortality in patients aged 50 years or older with a FNF. The final models must be externally validated to assess generalizability to other populations, and prospectively evaluated in the process of shared decision-making.
Objective: We sought to evaluate the association between prior spontaneous preterm delivery and subsequent pregnancy outcome.
Study Design: A total of 1711 multiparous women with singleton gestations ...were prospectively evaluated at 23 to 24 weeks’ gestation. Prior pregnancies were coded for the presence or absence of a prior spontaneous preterm delivery. If a prior spontaneous preterm delivery had occurred, the gestation of the earliest prior delivery (13-22, 23-27, 28-34, and 35-36 weeks’ gestation) was recorded. Current gestations were categorized as spontaneous preterm delivery at <28, <30, <32, <35, or <37 weeks’ gestation. The risk of spontaneous preterm delivery in the current gestation was determined on the basis of the occurrence, gestational age, and cause of the earliest prior spontaneous preterm delivery.
Results: The incidences of spontaneous preterm delivery before 28, 30, 32, 35, and 37 weeks’ gestation were 0.8%, 1.1%, 1.9%, 5.1%, and 11.9%, respectively. Those with a prior spontaneous preterm delivery carried a 2.5-fold increase in the risk of spontaneous preterm delivery in the current gestation over those with no prior spontaneous preterm delivery (21.7% vs 8.8%;
P ≤ .001). Gravid women with an early prior spontaneous preterm delivery (23-27 weeks’ gestation) had a higher risk of recurrent spontaneous preterm delivery (27.1% vs 8.8%;
P ≤ .001). Prior spontaneous preterm delivery was more closely associated with subsequent early spontaneous preterm delivery at <28 weeks’ gestation (relative risk, 10.6) than for spontaneous preterm delivery overall (relative risk, 2.5). An early prior spontaneous preterm delivery (23-27 weeks’ gestation) was most highly associated with early spontaneous preterm delivery (<28 weeks’ gestation) in the current gestation (relative risk, 22.1). The relationship between prior spontaneous preterm delivery and current outcome was not as strong for those with a very early spontaneous preterm delivery (13-22 weeks’ gestation). Prior spontaneous preterm delivery caused by preterm premature rupture of the membranes and preterm labor was significantly associated with similar outcomes in the current gestation (
P < .001).
Conclusion: Prior spontaneous preterm delivery is highly associated with recurrence in the current gestation. An early prior spontaneous preterm delivery is more predictive of recurrence and is most highly associated with subsequent early spontaneous preterm delivery. (Am J Obstet Gynecol 1999;181:1216-21.)
To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk ...HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks RRs) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.
In this small blinded randomized controlled multicenter trial, the authors have evaluated the effect of deep neuromuscular blockade
(NMB) on surgical conditions during-low pressure pneumoperitoneum ...(PNP) laparoscopic donor nephrectomy. Previous evidence
supports that low-pressure PNP (6 mmHg) reduces post-operative pain, but sometimes may restrain visibility and surgical access.
By applying deep NMB authors were able to demonstrate lower post-operative opiate requirement besides improvement in surgical
conditions. Although not significant, insufflation pressures were lower in the deep NMB group. In four patients in the moderate NMB
group, major intraoperative complications occurred in whom two required conversion to open procedure have had occurred. Given
the relatively high incidence of intraoperative complications and conversions to open donor nephrectomy, the use low-pressure PNP
with moderate NMB may compromise safety during surgery.
The purpose of this study was to evaluate the associations between measured amniotic fluid volume and outcome after preterm premature rupture of membranes (PROM).
This was a secondary analysis of 290 ...women, with singleton pregnancies, who participated in a trial of antibiotic therapy for preterm PROM at 24
0 to 32
0 weeks. Each underwent assessment of the 4 quadrant amniotic fluid index (AFI) and a maximum vertical fluid pocket (MVP) before randomization. The impact of low AFI (<5.0 cm) and low MVP (<2.0 cm) on latency, amnionitis, neonatal morbidity, and composite morbidity (any of death, RDS, early sepsis, stage 2-3 necrotizing enterocolitis, and/or grade 3-4 intraventricular hemorrhage) was assessed. Logistic regression controlled for confounding factors including gestational age at randomization, GBS carriage, and antibiotic study group.
Low AFI and low MVP were identified in 67.2% and 46.9% of women, respectively. Delivery occurred by 48 hours, 1 and 2 weeks in 32.4%, 63.5% and 81.7% of pregnancies, respectively. Both low AFI and low MVP were associated with shorter latency (
P < .001), and with a higher rate of delivery at 48 hours, 1, and 2 weeks (
P = .02 for each). However, neither test offered significant additional predictive value over the risk in the total population. Low AFI and low MVP were not associated with increased amnionitis. After controlling for other factors, both low MVP and low AFI were associated with shorter latency (
P ≤ .002), increased composite morbidity (
P = .03), and increased RDS (
P ≤ .01), but not with increased neonatal sepsis (
P = .85) or pneumonia (
P = .53). Alternatively, after controlling for fluid volume, gestational age, and GBS carriage, the antibiotic study group had longer latency, and suffered less common primary outcomes and neonatal sepsis.
Oligohydramnios should not be a consideration in determining which women will be candidates for expectant management or antibiotic treatment when it is identified at initial assessment of preterm PROM remote from term.
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