Machine Learning to Predict Outcomes of Fetal Cardiac Disease: A Pilot Study.

Prediction of outcomes following a prenatal diagnosis of congenital heart disease (CHD) is challenging. Machine learning (ML) algorithms may be used to reduce clinical uncertainty and improve prognostic accuracy. We performed a pilot study to train ML algorithms to predict postnatal outcomes based on clinical data. Specific objectives were to predict (1) in utero or neonatal death, (2) high-acuity neonatal care and (3) favorable outcomes. We included all fetuses with cardiac disease at Sunnybrook Health Sciences Centre, Toronto, Canada, from 2012 to 2021. Prediction models were created using the XgBoost algorithm (tree-based) with fivefold cross-validation. Among 211 cases of fetal cardiac disease, 61 were excluded (39 terminations, 21 lost to follow-up, 1 isolated arrhythmia), leaving a cohort of 150 fetuses. Fifteen (10%) demised (10 neonates) and 65 (48%) of live births required high acuity neonatal care. Of those with clinical follow-up, 60/87 (69%) had a favorable outcome. Prediction models for fetal or neonatal death, high acuity neonatal care and favorable outcome had AUCs of 0.76, 0.84 and 0.73, respectively. The most important predictors for death were the presence of non-cardiac abnormalities combined with more severe CHD. High acuity of postnatal care was predicted by anti Ro antibody and more severe CHD. Favorable outcome was most predicted by no right heart disease combined with genetic abnormalities, and maternal medications. Prediction models using ML provide good discrimination of key prenatal and postnatal outcomes among fetuses with congenital heart disease.

Utility of ultrasound assessment in management of pregnancies with preterm prelabor rupture of membranes.

OBJECTIVES: To evaluate the utility of ultrasound markers in the management of pregnancies complicated by preterm prelabor rupture of membranes (PPROM) between 23 + 0 and 33 + 6 weeks' gestation, and to assess the ability of ultrasound markers to predict adverse neonatal outcomes. METHODS: This was a retrospective cohort study of all patients with PPROM between 23 + 0 and 33 + 6 weeks' gestation and latency period (PPROM to delivery) > 48 h, who delivered before 34 weeks' gestation at a tertiary referral center between 2005 and 2017. All patients underwent a non-stress test daily and an ultrasound scan twice a week for assessment of amniotic fluid volume, biophysical profile (BPP) and umbilical artery (UA) pulsatility index (PI). In patients with suspected fetal growth restriction, fetal middle cerebral artery (MCA)-PI was also assessed and the cerebroplacental ratio (CPR) calculated. The last ultrasound examination performed prior to delivery was analyzed. We compared the characteristics and outcomes between women who were delivered owing to clinical suspicion of chorioamnionitis and those who were not delivered for this indication. The primary objective was to evaluate the utility of ultrasound in the management of patients with PPROM. The secondary objective was to assess the diagnostic performance of ultrasound markers (BPP score < 6, oligohydramnios, UA-PI > 95th percentile, MCA-PI < 5th percentile, CPR < 5th percentile) for the prediction of composite adverse neonatal outcome, which was defined as the presence of one or more of: perinatal death, respiratory distress syndrome, periventricular leukomalacia, intraventricular hemorrhage Grade 3 or 4, necrotizing enterocolitis, hypoxic ischemic encephalopathy, neonatal sepsis or neonatal seizures. RESULTS: A total of 504 women were included in the study, comprising 120 with suspected chorioamnionitis and 384 without. Women with suspected chorioamnionitis, compared with those without, were less likely to be nulliparous (34.2% vs 45.3%; P = 0.03) and more likely to have fever (50.8% vs 2.6%; P < 0.001) and be delivered by Cesarean section (69.2% vs 42.4%; P < 0.001), mainly owing to a history of previous Cesarean section (18.3% vs 9.1%; P = 0.005) and to having non-reassuring fetal heart rate tracings (32.5% vs 14.6%; P < 0.001). No significant differences were found between the two groups with regard to the median amniotic fluid volume, overall BPP score, BPP score < 6, MCA-PI or CPR. Median UA-PI was slightly higher in the suspected-chorioamnionitis group, yet the incidence of UA-PI > 95th percentile was similar between the two groups. There was a higher incidence of composite adverse neonatal outcome in the group with suspected chorioamnionitis than in the group without (78.3% vs 64.3%, respectively; P = 0.004). However, on logistic regression analysis, none of the ultrasound markers evaluated was found to be associated with chorioamnionitis or composite adverse neonatal outcome, and they all had a poor diagnostic performance for the prediction of chorioamnionitis and composite adverse neonatal outcome. CONCLUSIONS: Commonly used ultrasound markers in pregnancies complicated by PPROM were similar between women delivered for suspected chorioamnionitis and those delivered for other indications, and performed poorly in predicting composite adverse neonatal outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome.

OBJECTIVE: The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease. METHODS: Three hundred and forty-nine pre- and post-menopausal women, aged 18 years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample. RESULTS: Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p<0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients. CONCLUSIONS: Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

Approach in glucocorticoid-induced osteoporosis prevention: results from the Italian multicenter observational EGEO study.

Glucocorticoid-induced osteoporosis (GIO) is the most frequent cause of secondary osteoporosis. GIO is linked to glucocorticoids (GC) daily assumption with maximum effect within first months of treatment and decreasing to basal levels as the therapy is discontinued. In Italy, primary prevention of GIO is suggested when GC therapy (prednisone >5 mg/day or equivalent) is taken for longer than 3 months. Lazio GISMO (Italian Group for Study and Diagnosis of Bone Metabolism Diseases) group organized the GC and Osteoporosis Epidemiology study (EGEO) to evaluate physician's approach in preventing GIO. The study involved 19 osteoporosis centers. Patients taking long-term GC therapy were recruited and information collected: medical history and anthropometric data, GC therapy, primary disease, physician's specialty, osteopororosis screening, and pharmacological intervention. The study included 1334 patients. Mean age was 63 ± 13 yr; 243 (18%) patients had a history of falls from standing position in the previous 12 months, 78 (35%) vertebral fractures, 91 (41%) fractures other than vertebral, 27 (12%) femoral fractures, and 27 (12%) multiple sites fractures. The molecules of GC more often prescribed were prednisone and 6-metil prednisolone. One thousand and forty patients (78%) were taking GC for more than 6 months. GC therapy was prescribed more frequently by rheumatologists (62%). Antiosteoporotic drugs for GIO prevention were prescribed in 431 patients (32%). Among the patients, only 27% (360) received calcium and vitamin D supplements, and 39% (319) treated by rheumatologists received anti-resorptive drugs. In conclusion, our data show that in Italy, as already described elsewhere, only a small subpopulation of GC-treated patients was supported by an anti-osteoporotic therapy, indicating the need to further stimulate awareness of both patients and specialists, prescribing GC therapy, to an appropriate and prompt GIO prevention.

Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies.

L-[1-13C]Leucine, [1-13C]glycine, L-[1-13C]phenylalanine, and L-[1-13C]proline were infused as a bolus into the maternal circulation of seven appropriate for gestational age at 30.3 +/- 3.0 wk and 7 intrauterine growth-restricted pregnancies at 26.5 +/- 1.0 wk gestation to investigate placental transport in vivo. Umbilical venous samples were obtained at the time of in utero fetal blood sampling at 450 +/- 74 sec from the bolus injection. In normal pregnancies the fetal/maternal (F/M) enrichment ratios for leucine (0.76 +/- 0.06) and phenylalanine (0.77 +/- 0.06) were higher (P < 0.01) than the F/M ratios for glycine (0.18 +/- 0.04) and proline (0.22 +/- 0.02). This suggests that these two essential amino acids rapidly cross the placenta in vivo. Compared with the essentials, both glycine and proline had significantly lower F/M enrichment ratios, which were not different from each other. The results support the hypothesis that amino acids with high affinity for exchange transporters cross the placenta most rapidly. In intrauterine growth-restricted pregnancies, the F/M enrichment ratio was significantly lower (P < 0.01) for L-[1-13C]leucine (0.76 +/- 0.06 vs. 0.48 +/- 0.07) and for L-[1-13C]phenylalanine (0.77 +/- 0.06 vs. 0.46 +/- 0.07) compared with appropriate for gestational age pregnancies reflecting impaired transplacental flux. The F/M enrichment ratio did not differ for [1-13C]glycine (0.18 +/- 0.04 vs. 0.17 +/- 0.03), and L-[1-13C]proline (0.22 +/- 0.02 vs. 0.18 +/- 0.04).

Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action.

The mode of action of Ecteinascidin-743 (ET-743), a marine tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata, which has shown very potent antitumour activity in preclinical systems and encouraging results in Phase I clinical trials was investigated at a cellular level. Both SW620 and LoVo human intestinal carcinoma cell lines exposed for 1 h to ET-743 progress through S phase more slowly than control cells and then accumulate in the G2M phase. The sensitivity to ET-743 of G1 synchronised cells was much higher than that of cells synchronised in S phase and even higher than that of cells synchronised in G2M. ET-743 concentrations up to four times higher than the IC(50) value caused no detectable DNA breaks or DNA-protein cross-links as assessed by alkaline elution techniques. ET-743 induced a significant increase in p53 levels in cell lines expressing wild-type (wt) (p53). However, the p53 status does not appear to be related to the ET-743 cytotoxic activity as demonstrated by comparing the drug sensitivity in p53 (-/-) or (+/+) mouse embryo fibroblasts and in A2780 ovarian cancer cells or the A2780/CX3 sub-line transfected with a dominant-negative mutant TP53. The cytotoxic potency of ET-743 was comparatively evaluated in CHO cell lines proficient or deficient in nucleotide excision repair (NER), and it was found that ET-743 was approximately 7-8 times less active in ERCC3/XPB and ERCC1-deficient cells than control cells. The findings that G1 phase cells are hypersensitive and that NER-deficient cells are resistant to ET-743 indicate that the mode of action of ET-743 is unique and different from that of other DNA-interacting drugs.

Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective delta opioid agonists, based on an extension of the message-address concept.

This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

Pharmacological profiles of selective non-peptidic delta opioid receptor ligands.

Several non-peptidic opioids have been synthesized recently as part of a program to develop selective delta receptor agonists. In this study, the affinities of a set of compounds for cloned delta and mu opioid receptors expressed in HEK 293 cell lines were determined by competition analysis of [3H]bremazocine binding to membrane preparations. All compounds studied exhibited high affinity and selectivity, with apparent dissociation constants in the range of 0.6-1.7 nM for the delta opioid receptor and 240-1165 nM for the mu opioid receptor. We next sought to determine which domain of the delta receptor was critical for mediating the highly selective binding by analysis of ligand affinities for mu/delta receptor chimeras. Receptor binding profiles suggested that a critical site of receptor/ligand interaction was located between transmembrane domain 5 (TM5) and TM7 of the delta receptor. Substitution of tryptophan 284, located at the extracellular surface of TM6, with lysine, which is found at the equivalent position in the mu opioid receptor, led to a spectrum of effects on affinities, depending on the ligand tested. Affinities of SB 219825 and SB 222941 were particularly sensitive to the substitution, displaying a 50-fold and 70-fold decrease in affinity, respectively. Activities of the delta receptor-selective agonists were tested in two functional assays. Brief exposure of HEK 293 cells expressing delta opioid receptors with selective ligands induced phosphorylation of MAP kinase, although the non-peptidic ligands were less efficacious than the enkephalin derivative DADL (Tyr-D-Ala-Gly-Phe-D-Leu). Similarly, chronic exposure of HEK 293 cells expressing delta opioid receptors with selective, non-peptidic ligands, with the exception of SB 206848, caused receptor down-regulation, however, the SB compounds were less efficacious than DADL.

Synthesis and NMR characterization of a novel class of thienomorphinans.

[formula: see text] Synthesis of four novel thieno derivatives 4-7 featuring the codeine skeletal backbone is reported. Characterization by 1H and 13C NMR is also discussed, along with binding profile for opioid receptors.

The impact of malnutrition on the quality of life in the elderly.

Malnutrition is a frequent condition, both widely represented in geriatric population and underestimated in diagnostic and therapeutic work-up, and is known to affect health status and life expectancy of elderly people. The unexpected weight loss is a pathological condition, recently classified in three different ways (sarcopenia, wasting and cachexia) according to criteria of nutritional intake, functional abilities and age-related body composition modifications, that is caused by social psychological and medical factors. In this review, the authors highlight the ways that, through malnutrition, could lead to an impairment of quality of life in elderly people. Notwithstanding the great impreciseness and confusion that surrounds the term 'quality of life', the authors focus their attention on the correlation existing with the recently occurring changes to patients' health status and life-style, analysing the relationship with frailty, failure to thrive and homeostatic balance failure syndrome. With the latter term, the authors introduce a pathological condition widely represented in the late stages of malnutrition that often evolves in multiple organ failure and lastly in the death.

Influence of obesity on cardiac mass and blood pressure in the elderly.

Obesity is a physical condition, related to abnormalities of glucose and insulin metabolism; it plays a substantial role in development of cardiovascular disease. The aim of this study was to establish the correlations among cardiac mass determined by echography according to the PENN Convention criteria (Devereux Index), blood pressure measured by ambulatory blood pressure monitoring (ABPM), and anthropometric indexes such as body mass index (BMI) and local adipose tissue distribution expressed as the waist to hip ratio (WHR). Two groups of subjects were selected, matched for age (67 +/- 2.5 years): 10 obese subjects with BMI = 34.5 +/- 2.8 and WHR = 1.02 +/- 0.004; and 10 non-obese subjects with BMI = 26.8 +/- 2.1 and WHR = 0.088 +/- 0.003. Statistical analysis was carried out by the Mann-Whitney U-Test, and linear regression analysis. The statistical analysis revealed a higher mean blood pressure (MBP) in the nonobese group (138.5 +/- 16.9 / 82.2 +/- 5.09 mmHg) compared to the obese subjects (131 +/- 15.3 / 84.29 +/- 11.72 mmHg), the difference was not significant (p > 0.05). Nevertheless, a significant difference was found in the left ventricular mass (LVM) and the LVM index (LVMI) of the two groups (p < 0.005) as follows: LVM(norm) = 224.55 +/- 50.59; LVM(ob) = 295.02 +/- 43.54; LVMI(norm) = 127.56 +/- 18.58; LVMI(ob) = 172.48 +/- 15.44. These results represent an evidence showing that obesity and blood pressure are two independent risk factors in the determination of the ventricular cardiac mass.

Role of aging in malnutrition and in restitution of nutritional parameters by tube feeding.

Aging and malnutrition are connected by social and pathological factors; many studies show that 60-80% of hospitalized elderly patients are malnourished. The aim of this study was to establish a correlation between age and nutritional parameters in malnourished, hospitalized, elderly patients before and after restitution by tube feeding (using Clintec chemicals) for 45 days, with a mean caloric contribution of 2670 +/- 235 Kcal/day. Twenty-three patients were examined, matched for age (80.59 + 8.35 years) and sex (11 females and 12 males). Patients affected by malignant, chronic or acute diseases that could directly increase cytokine production (TNF-alpha, IL-1, etc.) were excluded. Anthropometric measurements were carried out always by the same operator using a fiberglass tape measure and a Harpenden skinfold caliper. Statistical analysis was carried out by ANOVA test and linear regression analysis. The main observations before and after tube feeding were the following: (i) Significant increases were found in serum albumin, triglyceride and cholesterol levels, whereas slightly increasing tendencies occurred, without reaching statistical significance, in serum transferrin levels, in triceps skinfold (TSF) and mid arm muscle circumference (MAMC) values. In malnourished patients close correlations were found between the age and serum albumin (r = 0.486; p = 0.022), as well as between age and MAMC (r = 0.576; p = 0.005), however, these correlations disappeared after tube feeding. These data show that age itself does not represent an important impediment for nutritional restitution; the possibilities of the latter appear to be dependent on the self-sufficiency and cognitive faculty of the patient, as measured by the activity of daily living (ADL), instrumental activity of daily living (IADL) and mini mental state evaluation (MMSE) scores (p < 0.005).

Baroreflex sensitivity in the elderly with silent myocardial ischemia.

In order to assess high-pressure baroceptor sensitivity and parasympathetic function in elderly patients with silent myocardial ischemia, we selected 45 inpatients in our geriatric unit for a prospective cohort study of patients with coronary heart disease. All patients were over 65 years of age (37 men and 8 women) and had coronary heart disease, documented by an angiographic study and electrocardiographic evidence of myocardial ischemia during exercise stress testing, performed according to the Bruce protocol. The subjects were divided in three subgroups: group 1 (22 patients) with electrocardiographic and echocardiographic history of myocardial infarction but no angina chest pain during exercise testing; group 2 (13 patients) with no exercise induced chest pain; and group 3 (10 patients) with exercise-induced chest pain. Baroceptor sensitivity was assessed in all subjects, by evaluating heart rate changes expressed in RR interval on the basis of changes in the mean arterial pressure during intravenous infusion of stepwise doses (50-100 and 150 microg) of phenylephrine hydrochloride. Heart rate changes were also evaluated during overshoot of the Valsalva maneuver (Valsalva max.), providing an index of parasympathetic activity. Our results showed that group two patients (only silent ischemia) had significantly (P>0.001) greater baroceptor sensitivity than the other two groups (group 2; 15.2+/-1.9 ms/mmHg; group 1: 10.0+/-1.7 ms/mmHg; and group 3: 9.8+/-1.7 ms/mmHg). Group two also showed a significant positive correlation (r=0.58; P<0.05) between baroceptor sensitivity and end-diastolic pressure and a significant inverse correlation (r=-0.672; P<0.05) between baroceptor sensitivity and the ejection fraction. Group 2 patients had a significantly longer RR interval than group 1 (P<0.05) and group 3 (P<0.05); a significant positive correlation (r=0.620; P<0.05) between Valsalva max. and end-diastolic pressure; and a significant inverse correlation (r=0.694; P<0.05) between Valsalva max. and the ejection fraction. Valsalva max. and baroceptor sensitivity correlated significantly in all three groups (group 1, r=0.707; P<0.001; group 2, r=0.94; P<0.001; and group 3; r=0.833; P<0.05). In conclusion our data suggest that elderly patients with silent ischemia appear to have an increased capacity for evoking parasympathetic reflexes that could inhibit pain perception.

Selective delta opioid receptor agonists for inflammatory and neuropathic pain.

In the last decade a number of selective and potent non-peptidic agents became available to explore the usefulness of the delta-opioid receptor in modulation of pain of different origins. As a continuing effort in this field, potent and selective delta-opioid agonists based on the pyrrolomorphinan framework have been designed, synthesised and characterised biologically in our laboratories. In animal models, a selected compound of interest, SB 235863, has proved the concept that selective delta-opioid agonists may have great potential as pain relief agents in inflammatory and neuropathic pain conditions. Importantly, such a compound was free of the unwanted side effects usually associated with narcotic analgesics such as morphine.

Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111.

BACKGROUND AND PURPOSE: Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists have been proposed as a novel therapeutic approach to Parkinson's disease. Main limitations of previous studies were the use of structurally similar compounds and the evaluation of their acute effects only. We report here on the acute and long-term antiparkinsonian effects of the novel compound 2-[3-[4-(2-chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl]-2-(morpholine-4-carbonyl)-indol-1-yl]-acetamide (NiK-21273) in comparison with the potent and selective NOP receptor antagonist SB-612111. EXPERIMENTAL APPROACH: Basic pharmacological properties of NiK-21273 were studied in cell lines and isolated tissues (mouse and rat vas deferens). Antiparkinsonian effects were studied in reserpinized mice and 6-hydroxydopamine hemilesioned rats under both acute and chronic administration protocols. KEY RESULTS: In vitro, NiK-21273 behaved as a potent (pA(2) 7.7) and selective NOP receptor antagonist. In vivo, it reduced hypokinesia in reserpinized mice at 0.1 and 1 but not 10 mg·kg(-1), whereas SB-612111 (0.01-1 mg·kg(-1)) provided a dose-dependent antiparkinsonian effect. NiK-21273 ameliorated motor performance in 6-hydroxydopamine hemilesioned rats at 0.5 and 5 but not 15 mg·kg(-1). SB-612111 replicated these effects in the 0.01-1 mg·kg(-1) range without loss of efficacy. Both antagonists synergized with L-DOPA at subthreshold doses. Chronic administration of NiK-21273 provided delayed improvement in baseline activity at 0.5 and 1.5 mg·kg(-1), although tolerance to the higher dose was observed. Conversely, SB-612111 (1 mg·kg(-1)) maintained its effects over time without modifying baseline activity. CONCLUSIONS AND IMPLICATIONS: NOP receptor antagonists provide motor benefit in parkinsonism models although the 'therapeutic' window and long-term effects may vary between compounds.

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha.

In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARα) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RARα, which forms only heterodimers with retinoic X receptor alpha, are also able to homo-oligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any self-association domain is sufficient to bestow a leukemogenic activity on RARα is still under investigation. In this work, we address this question using two different X-RARα chimeras, where X represents the coiled-coil domain of PML (CC-RARα) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RARα). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RARα biological properties, but CC-RARα is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RARα chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARα into an oncogenic protein.