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While postoperative pain management was shown to reduce unwanted physiological and emotional outcomes, pediatric postoperative pain management remains suboptimal. Medical-clowns were shown to be beneficial in many medical contexts including reduction of stress, anxiety and pain. This study was set to assess the effectiveness of medical-clowns on pediatric postoperative pain reduction. Children age 4 or above, planned for elective hernia repair surgery were recruited. Children were randomly divided to a control or medicalclown escorted groups. Demographical and clinical data were collected using questionnaires and electronic sheets. Children escorted by clowns reported lower levels of pain upon admittance, discharge and 12- hours post-surgery. Statistically significant reduction of parental distress and significantly higher serum cortisol levels were observed in the clown-therapy group. Although small, our study supports the possibility that preoperative medical-clown therapy might be a cheap, safe and yet beneficial method for postoperative pain reduction., Competing Interests: Conflict of interests: the authors declare no potential conflict of interests., (©Copyright: the Author(s), 2019.)

Objective : We explored the desire to be a parent, attachment avoidance and their associations in a sample of gay men and lesbians and their heterosexual counterparts. Background : Previous research suggested a link between minority stress and higher attachment avoidance. However, the association between attachment avoidance and parenthood desires as a function of sexual orientation was not studied. Methods : The sample was composed of 883 community-dwelling participants (51.1% women, 30.57% identified as gay men and 14.15% as lesbians) that were recruited through convenience sampling. Results : Gay men and lesbians reported less desire to be parents than their heterosexual counterparts and higher attachment avoidance. However, the association between attachment avoidance and less desire for parenthood was moderated by sexual orientation, such that the correlation between attachment avoidance and lesser desire for parenthood was only found for heterosexual men and women. Conclusion : These findings pinpoint the potential vulnerability of gay men and lesbians to develop greater attachment avoidance and the impact of sexual orientation on the association between attachment avoidance and the desire to be a parent. The moderation effect is discussed in terms of the specific reproductive alternatives available to gay men and lesbians vs. the heterosexual population.

There have been significant advances in the care of burns over the past decade. As a result of the improved survival of burn patients, attention has shifted to the optimized management of their wounds. Traditionally, autografts have been described as the gold standard treatment in cases of deep second- and third-degree burn wounds; however, they are limited especially in large surface area burns. As such, advancements have been made in the development of biologic dressings, which attempt to mimic the function of the lost epidermis and/or dermis. The ideal biologic dressing is nontoxic, lacks antigenicity, is immunologically compatible, and is sterile. Additionally, easy storage conditions, long shelf lives, and reasonable costs are key determinants of whether biologic dressings may truly be widely used in the clinical setting. Biologic dressings serve an important role as skin substitutes in the setting of acute burn injury. This review aims to summarize the multitude of available biologic dressings and their applications. METHODS: The PubMed and Google Scholar databases were searched for the following terms either alone or in combination: "burn injury," "biologic membrane," "skin substitutes," "biosynthetic dressings," and "acellular membrane."

Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3 -internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for this effect remain unknown. Using mouse APL models, we unexpectedly demonstrate that FLT3 -ITD severely blunts ATRA response. Remarkably, although the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is blunted, as is PML nuclear body reformation and activation of P53 signaling. Critically, the combination of ATRA and arsenic fully rescues therapeutic response in FLT3- ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL eradication. Moreover, arsenic targeting of normal PML also contributes to APL response in vivo. These unexpected results explain the less favorable outcome of FLT3 -ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination., (© 2019 by The American Society of Hematology.)

Systematic physical and electrochemical characterizations revealed unique positive multifunction of a polymeric salen-type nickel(II) complex, poly[Ni(CH 3 -salen)], as an additive for conventional cathodes in lithium-ion batteries. Due to its promising electrochemical and mechanical properties, combined with its unique three-dimensional weblike electron-network structure, the redox-active-organometallic polymer can eliminate conductive carbon and replace a significant portion of the poly(vinylidene fluoride) (PVdF) binder that has been used in conventional LiFePO 4 cathodes. By replacing such electrochemically inactive components (i.e., carbon and PVdF), LiFePO 4 cathodes with poly[Ni(CH 3 -salen)] deliver improved energy density compared with the conventional LiFePO 4 cathode. Facile electron transfer via large-area contact at polymer/LiFePO 4 interfaces significantly accelerates charge-transfer reactions and consequently improves the rate capability of the cathodes. In addition, unlike PVdF, poly[Ni(CH 3 -salen)] retains steady Young's modulus values after immersing in an electrolyte solvent, which enhances the mechanical integrity of the cathodes during the cycling of battery cells and thereby improves their cycle life. The unique multifunction of the poly[Ni(CH 3 -salen)] will be of broad interest for its application in next-generation energy-storage devices.

Individuals with schizophrenia display substantial deficits in neurocognition, resulting in poor daily functioning and disability. Recent reports have suggested that neurocognitive dysfunction in this population is linked to increased inflammation. However, there is paucity of evidence supporting this link, as well as lack of information about the putative link of inflammation to daily functioning. We examined neurocognition (MCCB) and daily functioning (SLOF), as well as inflammatory markers (TNF-α, IL-6, IL-1β, and IL-12p70) in 41 individuals with schizophrenia. Poor neurocognition was significantly associated with increased peripheral TNF-α and IL-12p70 (r = -0.44 and r = -0.38, respectively, controlling for BMI, depression and antipsychotic medication). Notably, difficulties with daily functioning were significantly associated with increased peripheral TNF-α (r = -0.51) and a trend with increased IL-12p70. Our findings support previous hypotheses linking neurocognitive impairment to increased inflammation in individuals with schizophrenia. Our results extend these associations in this population, linking inflammation to poor daily functioning in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Zinc metallochaperones (ZMC) are a new class of anticancer drugs that reactivate zinc-deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53-mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings preclinically. We further sought to innovate the formulation of ZMCs to improve efficacy. Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted preclinical pharmacokinetic, pharmacodynamic, and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation. Results: In vitro , cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo pharmacokinetic studies indicate that ZMCs have a short half-life (< 30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc-deficient allele (p53 R172H ) while having no effect in mice expressing a non-zinc-deficient allele (p53 R270H ). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1. Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics, indicating that a brief period of p53-mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation. Clin Cancer Res; 24(18); 4505-17. ©2018 AACR ., (©2018 American Association for Cancer Research.)

While the survival rate of children with cancer is increasing, preserving fertility for prepubertal boys is still a challenge. Although intracytoplasmic sperm injection (ICSI) using frozen sperms has revolutionized infertility treatment, it is not applicable for the patients who undergo chemotherapy before puberty since spermatogenesis has not begun. Therefore, preserving spermatogonial stem cells (SSCs) as an experimental option can be provided to prepubertal patients at a risk of damage or loss of their SSCs due to cancer treatments and developmental or genetic disorders. Using frozen SSCs in testicular tissue, successful SSC autotransplantation in mouse and nonhuman primates has shown a promising future for SSC-based cell therapy. Cryopreservation of testicular tissue containing SSCs is the first step to translate SSC-based cell therapy into clinical male infertility treatment, and in the investigation into SSCs, it is very important to evaluate their quantity and functionality during this process. This systematic review summarizes the published data on cryopreservation techniques in human testis tissue for potential utilization in future clinical applications., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: Recent advances in the preservation and processing of amnion/chorion tissue have dramatically increased the bioavailability of these wound healing factors as well as the shelf life of their related tissue products, allowing for a surge in clinical use. Many studies, including basic science, clinical trials, and randomized controlled trials, have emerged examining the biologic properties of amnion/chorion membrane products and their efficacy in wound healing., Objective: A literature review was conducted regarding the safety and efficacy of amniotic membrane adjuncts., Methods: The PubMed and MEDLINE databases were queried and sorted based on clinical trials with publication dates ranging from 2013 to 2017. Only studies pertaining to human subjects were included for review., Results: Amnion/chorion membranes have been studied in the treatment of burns, diabetic foot ulcers, fistulas, ocular defects, and venous leg ulcers, among other wounds. Amnion/chorion allografts were found to be beneficial in the setting of difficult-to-heal fistulas and were effective in treating diabetic and venous ulcers when combined with standard therapy., Conclusions: Overall, clinical trials have demonstrated that patients treated with amniotic membrane products have increased rates of wound healing compared with the standard of care. Additional trials are needed to examine more amnion/chorion membrane products.

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as "reactivating" mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells' response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials.

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Hair loss is a complex problem that generates significant concern for those who are affected. Patients seeking medical treatments have limited options, and are increasingly turning to natural therapies. A novel nutraceutical product containing a proprietary Synergen Complex® composed of standardized, active botanicals with potent anti-inflammatory, adaptogenic (anti-stress), antioxidant, and dihydrotestosterone-inhibiting properties has been developed to improve hair growth and hair quality. The objective of this 6-month randomized, double-blind, placebo-controlled study was to assess the ability of this oral supplement (Nutrafol® Women's Capsules) to strengthen and promote the growth of hair in adult women with self-perceived thinning. Enrolled subjects were randomized to receive active treatment (n=26) or placebo (n=14). The primary endpoint in this study was a statistically significant increase in the number of terminal and vellus hairs based on phototrichograms obtained through macrophotography analysis. Daily intake of the nutraceutical supplement resulted in a significant increase in the number of terminal and vellus hairs in the target area at day 90 and day 180 vs placebo (P less than 0.009). Blinded Investigator Global Hair Assessments revealed significant improvements in hair growth (P equals 0.016) and overall hair quality (P equals 0.005). A significant percentage of subjects receiving active treatment also reported improvement in hair growth, volume, thickness, and hair growth rate, as well as decreased anxiety and other wellness parameters. There were no reported adverse events., Conclusion: This nutraceutical supplement safely and effectively promoted hair growth in women with self-perceived thinning. It provides a multi-targeted therapeutic approach to hair loss by addressing micro-inflammation, stress, and oxidative damage with clinically tested, standardized, and bio-optimized phytoactive ingredients. ClinicalTrials.gov: NCT03206567 J Drugs Dermatol. 2018;17(5):558-565.

Background: African American men experience increases in smoking during the young adult transition. Exposure to childhood adversity, a risk factor which disproportionately affects African American men, has been identified as a robust precursor to health risk behavior in general and cigarette smoking in particular. The intermediate mechanisms that transmit the influence of early adversity to smoking behavior are not well understood., Purpose: We tested a model of the escalation of smoking behaviors among young adult African American men, investigating sleep disturbance and delayed reward discounting as intermediate factors linking adverse childhood experiences with smoking., Methods: Hypotheses were tested with three waves of data (M age-T1  = 20.34, M age-T2  = 21.92, M age-T3  = 23.02) from 505 African American men living in rural counties in South Georgia. Men provided self-report data on their adverse childhood experiences, sleep problems, and smoking behavior using audio-assisted computer self-interviews. Men also completed a computer-based delayed reward discounting task., Results: Structural equation modeling analyses supported our hypotheses: Adverse childhood experiences predicted poor sleep adequacy, which forecast increases in delayed reward discounting; discounting, in turn, predicted increased smoking. Significant indirect pathways were detected linking adversity to discounting via sleep adequacy and linking sleep adequacy to smoking via discounting., Conclusions: Prevention and intervention researchers can draw on these findings to develop programs that focus on sleep adequacy to reduce smoking in African American men exposed to childhood adversity.

Hair loss affects millions of men and women of all ages and ethnicities, impacting appearance, social interactions, and psycho-emotional well-being. Although a number of options are available, they are limited, carry a potential risk of side effects, and none have proven to be comprehensive for treatment of hair loss. Across the spectrum of hair loss disorders, there has long been a segmentation into distinct mechanisms, driving the main trend in current therapeutics to focus on targeting single molecules or pathways. However, research points to similar dysregulation of intrinsic signaling pathways within follicle physiology that span the hair loss disorder spectrum - with a common inflammatory component identified in most hair loss pathogenesis, including that of androgenetic alopecia (AGA).

J Drugs Dermatol. 2017;16(11 Suppl):s135-140.

Hair loss is a complicated problem that causes significant concern for those who are affected. Patients seeking medical treatment have limited options that include topical minoxidil and oral finasteride. While these treatments are backed by long term clinical use and research outcomes, many patients find topical minoxidil difficult to incorporate into their daily routine and some are concerned with the side effects associated with finasteride. In the office setting, patients may be treated with more invasive procedures such as platelet-rich plasma injections (PRP) and hair transplantation, treatments that often must be repeated and can lead to a costly investment. Consumers are increasingly interested in natural treatments for hair loss. Many turn to basic supplements only to be disappointed when they fail to deliver due to lack of standardization and efficacy. In this paper we review the benefits of a nutraceutical containing a specific blend of highly purified, standardized, bio-optimized, and bioavailable botanical extracts to treat hair loss. These phytoactives were selected because of their diverse multi-modal biologic activity against inflammation, DHT, stress mediators, oxidative damage, and intermediary signaling cascades. This supplement represents a paradigm shift as it addresses not only the factors that trigger hair loss but the downstream mediators of inflammation as well. Multi-center clinical studies are currently underway to confirm the efficacy and benefits of this unique nutraceutical.

J Drugs Dermatol. 2017;16(11 Suppl):s141-148.

In acute myeloid leukemia (AML), a translocation between chromosomes 8q22 and 21q22 leads to the RUNX1-RUNXT1 fusion gene which, in the absence of a concomitant KIT mutation, generally portends a more favorable prognosis. Translocations at 21q22, other than those involving 8q22, are uncommon, and the specific prognostic and therapeutic implications are accordingly limited by the small number of reported cases. In this report, we describe the case of a 67-year-old gentleman who presented with AML harboring t(14;21)(q23;q22). Subsequent molecular analysis revealed mutations in RUNX1, ASXL1, and SF3B1, with translocation breakpoints identified within SYNE2 on chromosome 14 and RUNX1 on chromosome 21. The functional consequence of the DNA fusion between SYNE2 and RUNX1 is unclear. Nonetheless, despite several adverse risk factors associated with this patient's AML, he achieved a long-lasting remission with standard chemotherapy alone, potentially suggestive of a novel favorable-risk translocation in AML involving 21q22., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD) 2 -KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosis in vitro (40%-70%) and tumor regressions in vivo Comparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer. Mol Cancer Ther; 16(8); 1445-55. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Vascular blowout syndrome (VBOS) secondary to neoplastic erosion is a dreadful complication of advanced stage malignancies that can compromise quality of life and overall prognosis in a fragile patient population. Endovascular therapy can offer minimally invasive, life-saving maneuvers both acutely and prophylactically. Four patients with end-stage malignancies eroding into various peripheral vascular beds with impending, threatened, and acute VBOS underwent successful endovascular management. Technical success was achieved in all patients with no perioperative morbidity or mortality. In all patients, endovascular intervention controlled life-threatening hemorrhage and facilitated adjunctive therapeutic modalities such as surgical tumor debulking and/or chemoradiation. In conclusion, our small case series demonstrates that endovascular therapy can offer safe and effective palliation of peripheral VBOS secondary to neoplastic erosion.

Objectives: We quantified the 28-day mortality effect of preexisting do-not-resuscitate orders in ICUs., Design: Longitudinal, retrospective study of patients admitted to five ICUs at a tertiary university medical center (Beth Israel Deaconess Medical Center, BIDMC, Boston, MA) between 2001 and 2008., Intervention: None., Patients: Two cohorts were defined: patients with do not resuscitate advance directives on day 1 of ICU admission and a control group comprising patients with no limitations of level of care on ICU day 1 (full code)., Measurements and Main Results: The primary outcome was mortality at 28 days after ICU admission. Of 19,007 ICU patients, 1,239 patients (6.5%) had a do-not-resuscitate order on the first day of ICU admission and survived 48 hours in the ICU. We matched those do-not-resuscitate patients with 2,402 patients with full-code status. Twenty-eight day and 1-year mortality were both significantly higher in the do-not-resuscitate group (33.9% vs 18.4% and 60.7% vs 40.2%; p < 0.001, respectively)., Conclusion: Do-not-resuscitate status is an independent risk factor for ICU mortality. This may reflect severity of illness not captured by other clinical factors, but the perceptions of the treating team related to do-not-resuscitate status could also be causally responsible for increased mortality in patients with do-not-resuscitate status.

Our understanding of the role of zinc in normal human physiology is constantly expanding, yet there are major gaps in our knowledge with regard to the function of zinc in wound healing. This review aims to provide the clinician with sufficient understanding of zinc biology and an up-to-date perspective on the role of zinc in wound healing. Zinc is an essential ion that is crucial for maintenance of normal physiology, and zinc deficiency has many manifestations ranging from delayed wound healing to immune dysfunction and impairment of multiple sensory systems. While consensus has been reached regarding the detrimental effects of zinc deficiency on wound healing, there is considerable discord in the literature on the optimal methods and true benefits of zinc supplementation.

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted., (© 2017 by The American Society of Hematology.)

TP53 is the most commonly mutated gene in cancer, with over half of all human cancers harboring a mutation in the gene. The p53 protein is a transcription factor that functions as a tumor suppressor, and a subset of its numerous roles include the arrest of proliferation, promotion of DNA repair, and induction of apoptosis in cells with severe DNA damage or stress. The vast majority of p53 mutations are single amino acid substitutions within the DNA binding domain, which either directly impede the protein's ability to bind DNA or destabilize the structure, resulting in misfolding. These missense mutant proteins are found at high levels due to loss of the MDM2 mediated regulation, and consequently serve as potential drug targets. Numerous pharmacological approaches have been investigated to restore wild type p53 function to these mutants (so-called reactivating mutant p53) with some entering in clinical trials while most have failed in early development. Recently, the field of cancer drug development has produced a number of new compounds that continue to advance this field, each with a different mechanism of action. Here we sought to review these compounds and approaches to reactivating mutant p53. Given the large number of patients with missense mutant p53 mutations, reactivating mutant p53 remains a highly sought after goal in developmental therapeutics., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Seasonal variations of 25-hydroxyvitamin D, PTH and calcium levels are not well characterized in primary hyperparathyroidism (PHPT). Our objectives were to characterize seasonal changes in these parameters in PHPT patients, and to assess whether these seasonal changes affect clinical decision making., Methods: This is a retrospective study based on the electronic medical records of Clalit Health service in the south of Israel between 2000 and 2012. Patients 18years and older with PHPT (PTH>upper limit of norm (ULN) and serum calcium>10.5mg%) were included. Patients with renal failure or on Thiazide diuretics were excluded. All serum levels of calcium, PTH and 25-hydroxyvitamin D were collected and then stratified according to season., Results: 792 patients were classified as PHPT (72.2% female) and had a total of 2659 PTH tests, 1395 25-hydroxyvitamin D tests and 7426 calcium test. Fifty six percent of 25-hydroxyvitamin D levels were <50nmol/L. Seasonality was demonstrated in all three parameters: mean 25-hydroxyvitamin D was 13% higher in the summer compared to the winter (P<0.001), median PTH values showed opposite trend with a fall of about 8.4% in summer compared to winter (P<0.001). Calcium levels were higher during the autumn with a rise of about 0.2mg/dL in the mean calcium levels compared to spring and summer (P<0.001). The odds ratio of calcium level above 11.5mg/dL is highest in the autumn (OR=1.275, P=0.018)., Conclusion: We show seasonal variation in serum 25-hydroxyvitamin D, PTH, and calcium levels in patients with PHPT. These seasonal variations cause transition to pathological values that may influence diagnosis and treatment of PHPT patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation., Significance: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461., (©2016 American Association for Cancer Research.)

Spermatogonial stem cell (SSC) loss due to cancer treatment, developmental disorder or genetic abnormality may cause permanent infertility. Cryopreservation of ejaculated sperm is an effective method of fertility preservation in adult males at risk of infertility. However this is not an option in pre-pubertal boys because spermatogenesis has not yet started, and it is difficult in adolescents who are not sexually mature. Therefore testicular tissue cryopreservation to preserve SSCs for future generation of spermatogenesis, either in vivo or in vitro, could be an option for these groups of patients. Although SSC transplantation has been successful in several species including non-human primates, it is still experimental in humans. There are several remaining concerns which need to be addressed before initiating trials of human SSC autotransplantation. Establishment of a testicular tissue banking system is a fundamental step towards using SSC technology as a fertility preservation method. It is important to understand the consultation, harvesting the testicular tissue, histological evaluation, cryopreservation, and long term storage aspects. We describe here a multidisciplinary approach to establish testicular tissue banking for males at risk of infertility., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Identifying infection in emergency department (ED) patients can be challenging. This study assesses the value that inflammatory and endothelial biomarkers add to clinical data when predicting infectious etiologies of abnormal vital signs (AVSs) in ED patients., Methods: This study was a prospective, observational cohort study of ED patients with AVSs at an urban, academic tertiary-care hospital, identified from March 1, 2013, to April 15, 2013. Collected blood samples were assayed for soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule 1, vascular cell adhesion molecule 1, plasminogen activator inhibitor 1, interleukin 6, sFlt-1, and procalcitonin. History and physical examination were abstracted from the ED documentation. The primary outcome, infectious etiology, was adjudicated by review of the hospital documentation. Three multivariate logistic regression models predicting infection were created using clinical data, biomarkers, and combined clinical data and biomarker assessments. Integrated discrimination improvement tested the discriminate value of the biomarker and combined models compared with the clinical data model., Results: We enrolled 115 patients: 49 determined to have an infection (43%) and 66 without (57%). All biomarkers were significantly associated with infection in univariate analysis. The best clinical model (area under the curve [AUC] = 0.76) included initial temperature (odds ratio [OR], 1.6; confidence interval [CI], 1.1-2.2) and history of fever (OR, 5.0; CI, 1.4-14). The best biomarker model (AUC, 0.82) predicting infection included sE-selectin (OR, 11.0; 95% CI, 1.6-74) and interleukin 6 (OR, 5.1; CI, 2.3-11.6). The combined clinical and biomarker model had an AUC of 0.88, with integrated discrimination improvement = 0.21, compared with the clinical model alone., Conclusion: Inflammatory and endothelial markers can improve the clinical identification of infection in ED patients with AVSs.

Background: Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes., Methods: Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity., Results: Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation., Conclusion: We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Testicular prosthesis placement is a useful important adjunctive reconstructive therapy for managing children with testicular loss or absence. Though these prostheses are functionless, experience has shown that they are extremely helpful in creating a more normal male body image and in preventing/relieving psychological stress in males with a missing testicle. With attention to details of implant technique, excellent cosmetic results can be anticipated in simulating a normal appearing scrotum.

Objective: An adverse effect of acid-suppression medications on the occurrence of Clostridium difficile infection (CDI) has been a common finding of many, but not all studies. We hypothesized that association between acid-suppression medications and CDI is due to the residual confounding in comparison between patients with infection to those without, predominantly from non-tested and less sick subjects. We aimed to evaluate the effect of acid suppression therapy on incidence of CDI by comparing patients with CDI to two control groups: not tested patients and patients suspected of having CDI, but with a negative test., Methods: We conducted a case-control study of adult patients hospitalized in internal medicine department of tertiary teaching hospital between 2005-2010 for at least three days. Controls from each of two groups (negative for CDI and non-tested) were individually matched (1:1) to cases by primary diagnosis, Charlson comorbidity index, year of hospitalization and gender. Primary outcomes were diagnoses of International Classification of Diseases (ICD-9)-coded CDI occurring 72 hours or more after admission., Results: Patients with CDI were similar to controls with a negative test, while controls without CDI testing had lower clinical severity. In multivariable analysis, treatment by acid suppression medications was associated with CDI compared to those who were not tested (OR = 1.88, p-value = 0.032). Conversely, use of acid suppression medications in those who tested negative for the infection was not associated with CDI risk as compared to the cases (OR = 0.66; p = 0.059)., Conclusions: These findings suggest that the reported epidemiologic associations between use of acid suppression medications and CDI risk may be spurious. The control group choice has an important impact on the results. Clinical differences between the patients with CDI and those not tested and not suspected of having the infection may explain the different conclusions regarding the acid suppression effect on CDI risk.

Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8(+) effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40(-/-) mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.

Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory to conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells of mice causes a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML). We characterized the effects of Nf1 loss on immature hematopoietic populations and investigated treatment with the MEK inhibitor PD0325901 (hereafter called 901). Somatic Nf1 inactivation resulted in a marked expansion of immature and lineage-committed myelo-erythroid progenitors and ineffective erythropoiesis. Treatment with 901 induced a durable drop in leukocyte counts, enhanced erythropoietic function, and markedly reduced spleen sizes in mice with MPN. MEK inhibition also restored a normal pattern of erythroid differentiation and greatly reduced extramedullary hematopoiesis. Remarkably, genetic analysis revealed the persistence of Nf1-deficient hematopoietic cells, indicating that MEK inhibition modulates the proliferation and differentiation of Nf1 mutant cells in vivo rather than eliminating them. These data provide a rationale for performing clinical trials of MEK inhibitors in patients with JMML and CMML.

Objective: Ovarian and testicular tissue cryopreservation are the only fertility preservation options for sexually immature individuals. Because of their experimental nature, it is important to determine safety and possible bundling with other medicallyindicated procedures., Study Design: Prospective observational., Results: Cryopreservation indications included cancer in 75 % of females and 50 % of males, while non-cancer indications included various hematological conditions. Similar numbers of females (12/28) and males (3/9) underwent prior chemotherapy. Females underwent laparoscopic (27/28) or robotic (1/28) approaches while incisional biopsy was used in males. Bundling of ovarian and testicular harvesting with other medicallyindicated procedures was performed in 42 % and 22 %, respectively. The operative time inclusive of bundled procedures was similar (1.6 ± 0.1 vs. 0.9 ± 0.3 h) but the discharge time was significantly longer for females than males (10.4 ± 0.6 vs. 4.6 ± 0.6 h, p<0.05) due to frequent bundling of medically-indicated procedures in females. All procedures were successfully completed without complications or significant blood loss., Conclusions: Pediatric gonadal tissue cryopreservation can be combined with other medically-indicated procedures to minimize the potential inconvenience, additional anesthetic risks, and costs.

Second malignant neoplasms (SMN) are therapy-induced malignancies and a growing problem in cancer survivors, particularly survivors of childhood cancers. The lack of experimental models of SMNs has limited understanding of their pathogenesis. It is currently not possible to predict or prevent this devastating late complication. Individuals with neurofibromatosis I (NF1) are at increased risk of developing therapy-induced cancers for unclear reasons. To model SMNs, we replicated clinical radiotherapy and delivered fractionated abdominal irradiation to Nf1(+/-) and wild-type mice. Similar to irradiated cancer survivors, irradiated wild-type and Nf1(+/-) mice developed diverse in-field malignancies. In Nf1(+/-) mice, fractionated irradiation promoted both classical NF1-associated malignancies and malignancies unassociated with the NF1 syndrome but typical of SMNs. Nf1 heterozygosity potentiated the mutagenic effects of irradiation, as evidenced by the significantly reduced survival after irradiation and tumor development that was often characterized by synchronous primary tumors. Interestingly, diverse radiation-induced tumors arising in wild-type and Nf1(+/-) mice shared a genetic signature characterized by monoallelic loss of Nf1 and the adjacent Trp53 allele. These findings implicate Nf1 loss as mediating tumorigenesis in a broad range of cell types and organs extending beyond the classical NF1 tumor histologies. Examining clinical SMN samples, we found LOH of NF1 in SMNs from non-NF1 patients. Nf1 heterozygosity confers broad susceptibility to genotoxin-induced tumorigenesis, and this paradigm serves as an experimental platform for future studies of SMNs.

Over the past several decades, improved technologies used in the care of hospitalized and outpatient pediatric populations have resulted in a decreased but still significant number of iatrogenic injuries. Children at the highest risk for cutaneous injury include those with the most immature skin barriers, such as neonates younger than 32 weeks of gestational age. Additional risk factors include low birth weight, increased length of hospital stay, and indwelling instrumentation. Also at risk are older children with compromised skin barriers owing to infectious disease (staphylococcal scalded skin syndrome), inflammatory disease (atopic dermatitis), drug eruptions, and inherited or acquired blistering disorders. This review highlights the presentation, course, and management of iatrogenic skin injury events in children., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and the metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea, and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared with white adipose tissue (WAT), PVAT and BAT from C57BL6/J mice fed a high-fat diet for 13 wk had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80 and CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b(+)/CD11c(+) macrophages in BAT (1.0%) compared with WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from inflammatory stress.

Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.

A sequence analysis-oriented binary search-like algorithm was transformed to a sensitive and accurate analysis tool for processing whole-genome data. The advantage of the algorithm over previous methods is its ability to detect the margins of both short and long genome fragments, enriched by up-regulated signals, at equal accuracy. The score of an enriched genome fragment reflects the difference between the actual concentration of up-regulated signals in the fragment and the chromosome signal baseline. The "divide-and-conquer"-type algorithm detects a series of nonintersecting fragments of various lengths with locally optimal scores. The procedure is applied to detected fragments in a nested manner by recalculating the lower-than-baseline signals in the chromosome. The algorithm was applied to simulated whole-genome data, and its sensitivity/specificity were compared with those of several alternative algorithms. The algorithm was also tested with four biological tiling array datasets comprising Arabidopsis (i) expression and (ii) histone 3 lysine 27 trimethylation CHIP-on-chip datasets; Saccharomyces cerevisiae (iii) spliced intron data and (iv) chromatin remodeling factor binding sites. The analyses' results demonstrate the power of the algorithm in identifying both the short up-regulated fragments (such as exons and transcription factor binding sites) and the long--even moderately up-regulated zones--at their precise genome margins. The algorithm generates an accurate whole-genome landscape that could be used for cross-comparison of signals across the same genome in evolutionary and general genomic studies.

Individual members of the retinoblastoma (Rb) tumor suppressor gene family serve critical roles in the control of cellular proliferation and differentiation, but the extent of their contributions is masked by redundant and compensatory mechanisms. Here we employed a conditional knockout strategy to simultaneously inactivate all three members, Rb, p107, and p130, in adult hematopoietic stem cells (HSCs). Rb family triple knockout (TKO) mice develop a cell-intrinsic myeloproliferation that originates from hyperproliferative early hematopoietic progenitors and is accompanied by increased apoptosis in lymphoid progenitor populations. Loss of quiescence in the TKO HSC pool is associated with an expansion of these mutant stem cells but also with an enhanced mobilization and an impaired reconstitution potential upon transplantation. The presence of a single p107 allele is sufficient to largely rescue these defects. Thus, Rb family members collectively maintain HSC quiescence and the balance between lymphoid and myeloid cell fates in the hematopoietic system.

Integrins, which are transmembrane receptors for extracellular matrix proteins, play a key role in cell survival, proliferation, migration, gene expression, and activation of growth factor receptors. Their functions and expression are deregulated in several types of cancer, including prostate cancer. In this article, we review the role of integrins in prostate cancer progression and their potential as therapeutic targets.

Alu sequences carry periodical pattern with CG dinucleotides (CpG) repeating every 31-32 bases. Similar distances are observed in distribution of DNA curvature in crystallized nucleosomes, at positions +/-1.5 and +/-4.5 periods of DNA from nucleosome DNA dyad. Since CG elements are also found to impart to nucleosomes higher stability when positioned at +/-1.5 sites, it suggests that CG dinucleotides may play a role in modulation of the nucleosome strength when the CG elements are methylated. Thus, Alu sequences may harbor special epigenetic nucleosomes with methylation-dependent regulatory functions. Nucleosome DNA sequence probe is suggested to detect locations of such regulatory nucleosomes in the sequences.

Myelodysplastic syndromes (MDS) are clonal stem cell hematologic disorders that evolve to acute myeloid leukemia (AML) and thus model multistep leukemogenesis. Activating RAS mutations and overexpression of BCL-2 are prognostic features of MDS/AML transformation. Using NRASD12 and BCL-2, we created two distinct models of MDS and AML, where human (h)BCL-2 is conditionally or constitutively expressed. Our novel transplantable in vivo models show that expression of hBCL-2 in a primitive compartment by mouse mammary tumor virus-long terminal repeat results in a disease resembling human MDS, whereas the myeloid MRP8 promoter induces a disease with characteristics of human AML. Expanded leukemic stem cell (Lin(-)/Sca-1(+)/c-Kit(+)) populations and hBCL-2 in the increased RAS-GTP complex within the expanded Sca-1(+) compartment are described in both MDS/AML-like diseases. Furthermore, the oncogenic compartmentalizations provide the proapoptotic versus antiapoptotic mechanisms, by activating extracellular signal-regulated kinase and AKT signaling, in determination of the neoplastic phenotype. When hBCL-2 is switched off with doxycycline in the MDS mice, partial reversal of the phenotype was observed with persistence of bone marrow blasts and tissue infiltration as RAS recruits endogenous mouse (m)BCL-2 to remain active, thus demonstrating the role of the complex in the disease. This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex. The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy.

Mouse models of acute promyelocytic leukemia have been generated through transgenic, knock-in, retroviral, and xenograft strategies. These models have been used to elucidate mechanisms underlying leukemogenesis. Among the areas investigated are the role of reciprocal fusions; effects of target cells, expression levels, and mouse strains; cooperating events; and restrictive and permissive factors. These models have also been used to gain insight into the effects of the immune system on leukemic cells and the mechanism of response to retinoic acid. Furthermore, preclinical studies utilizing these mice have advanced therapy for myeloid leukemia.

Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.