The PML domain of PML–RARα blocks senescence to promote leukemia

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein–retinoic acid receptor α (PML–RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML–RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19^ARF cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx–histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations involving retinoic acid receptor alpha (RARα) with a limited number of translocation partners. A common feature of APL-promoting fusion proteins is their ability to self-associate. Indeed, previous studies have shown that fusion of RARα with self-associating domains is sufficient to render RARα leukemogenic (1). In APL patients, the predominant leukemogenic protein found in 95–99% of cases is the result of the fusion of promyelocytic leukemia protein (PML) with RARα (human PML–RARα; hPR) (2, 3). RARα and PML are regulatory proteins implicated in multiple aspects of differentiation and development (4) and apoptosis and cellular senescence (5, 6), respectively. Despite speculation, the relevance of senescence in APL is not fully understood (7, 8).Current mouse models recapitulate many key features of the human disease, including a malignant promyelocytic phenotype and sensitivity to all-trans retinoic acid (ATRA), but suffer from incomplete penetrance and long latency until disease presentation (1, 9, 10). We reasoned that the relatively low leukemogenic activity of hPR in mice might be due to modest sequence identity between human and mouse PML (PML: 63% identity; RARα: 98% identity). Consistent with this notion, we have designed an “experimental oncoprotein” corresponding to the fusion of mouse PML with RARα (mPR), which produced myelocytic leukemia similar to hPR-induced murine APL (10) but with higher penetrance and shorter latency periods. Notably, expression of mPR disrupted PML nuclear bodies (PML-NBs), phenocopying hPR-induced APL (11, 12). We show here that senescence-related up-regulation of p21 and p19 is completely lost in primary murine bone marrow cells upon expression of mPR. Furthermore, we find that the assembly of the death domain associated protein (Daxx)–alpha thalassemia/mental retardation syndrome X-linked (ATRX) complex at PML-NBs is disrupted by mPR expression, implicating this PML–ATRX–Daxx (PAX) complex in cellular senescence and tumor suppressor activity for PML (13). This study provides experimental evidence for the relevance of PML-NB disruption in APL genesis.     

Colorectal Cancer Screening Among American Indians in a Pacific Northwest Tribe: Cowlitz Tribal BRFSS Project, 2009–2010

Objectives

Colorectal cancer (CRC) screening is low among American Indians (AIs). We describe the demographics, health status, prevalence of modifiable CRC risk factors, and use of CRC screening modalities in a Pacific Northwest AI tribe.

Methods

We conducted a survey among Cowlitz tribal members using a Behavioral Risk Factor Surveillance System (BRFSS) questionnaire. We analyzed demographic, health status, behavioral risk factor, and CRC screening variables. Using the Washington State 2010 BRFSS, we compared tribal members with non-Hispanic white (NHW) people. We used logistic regression to examine factors associated with CRC screening for tribal members.

Results

A greater proportion of tribal members than NHW people reported living below the federal poverty level (12% vs. 7%, p=0.013). A greater proportion of tribal members than NHW people aged ≥50 years had poor self-reported health (27% vs. 16%, p=0.006) and were without health insurance (12% vs. 6%, p=0.004). A greater proportion of tribal members than NHW people had a fecal occult blood test within the past year (20% vs. 13%, p=0.006). Being 60–69 years of age (odds ratio [OR] = 2.6, 95% confidence interval [CI] 1.4, 4.9), ≥70 years of age (OR=2.2, 95% CI 1.1, 4.5), and having a personal health-care provider (OR=3.7, 95% CI 1.4, 9.6) were associated with increased screening adherence in tribal members.

Conclusion

Data from the Cowlitz Tribal BRFSS demonstrate that members are receiving CRC screening in the same proportions as NHW people despite lower sociodemographic and health status indicators among members. Unique characteristics of the tribe likely contribute to this finding.Cancer is the second leading cause of death among American Indian/Alaska Native (AI/AN) people; cardiovascular disease is the leading cause of death.¹ Overall, colorectal cancer (CRC) is the third most common cancer among AI/ANs behind prostate and lung cancer for men and breast and lung cancer for women.^2,3 In the most recent “Annual Report to the Nation on the Status of Cancer,” the incidence of CRC decreased among men and women in all racial/ethnic groups except AI/ANs.⁴Based on the Surveillance, Epidemiology, and End Results (SEER) program, the incidence of CRC is lower for AI/AN people than for those in other racial/ethnic groups.⁵ However, regional diversity in CRC incidence and racial misclassification can bias these nationwide estimates.^3,6,7 One strategy to overcome these biases is to link Indian Health Service (IHS) records with state cancer registries. Using the linkage strategy, researchers in the Pacific Northwest have found that the incidence of CRC is greater, and “one- and five-year CRC-related survival is lower among Pacific Northwest AI/ANs than among non-Hispanic white (NHW) people”⁷ (Unpublished thesis. Peterson PS. Colorectal cancer survival among American Indian and Alaska Native people in the Pacific Northwest. Oregon Health and Science University, 2011). Thus, investigations are needed to understand CRC screening patterns in this region, as well as barriers to screening that are unique to these tribal communities.Self-reported history of CRC screening is lower among AI/ANs than among NHW people.⁸ IHS Government Performance and Results Act (GPRA) data indicate improvement in CRC screening adherence among AI/ANs nationwide; however, these numbers are significantly lower than the Healthy People 2020 target of 70.5%.^9,10 According to GPRA 2010 data, the percentage of CRC screening adherence among IHS tribal users in the Pacific Northwest aged ≥50 years was 38%.¹⁰CRC screening behaviors vary regionally and are influenced by a complex set of sociodemographic, health-care-access, and cultural factors.^11–13 Among Northern Plain and Southwest AIs, Perdue et al. found an inverse association between cultural identity measures and screening by endoscopy or colonoscopy, but no trend with fecal occult blood tests (FOBTs).¹¹ In a study conducted in Alaska and the Southwest, researchers demonstrated that age >60 years, state of residence, urban residence, higher education, family history of CRC, former smoking, multiple medical conditions, English language spoken at home, and higher income were factors associated with an increase in age-appropriate CRC screening.¹² In another study conducted among AIs in North Carolina, self-rated health status, nonsmoking, and physical activity were associated with CRC screening.¹³While progress has been made, disparities persist in CRC screening, incidence of CRC cases, and CRC-related mortality in AI/ANs nationwide, including in the Pacific Northwest.^2–10 To date, no published research has addressed factors associated with CRC screening in Pacific Northwest tribes. The Cowlitz Tribal Behavioral Risk Factor Surveillance System (BRFSS) Project 2009–2010 provided a unique opportunity to investigate the health information of a tribe that has not been previously studied and to gain a better understanding of factors associated with cancer screening behaviors in this at-risk population.     

Screening for autism spectrum disorders: state of the art in Europe

A large number of studies have reported on the validity of autism spectrum disorder (ASD) screening procedures. An overall understanding of these studies’ findings cannot be based solely on the level of internal validity of each, since screening instruments might perform differently according to certain factors in different settings. Europe has led the field with the development of the first screening tool and first prospective screening study of autism. This paper seeks to provide an overview of ASD screening studies and ongoing programmes across Europe, and identify variables that have influenced the outcomes of such studies. Results show that, to date, over 70,000 children have been screened in Europe using 18 different screening procedures. Differences among findings across studies have enabled us to identify ten factors that may influence screening results. Although it is impossible to draw firm conclusions as to which screening procedure is most effective, this analysis might facilitate the choice of a screening method that best fits a specific scenario, and this, in turn, may eventually improve early ASD detection procedures.     

Human and monkey infant attention to dynamic social and nonsocial stimuli

The present study explored behavioral norms for infant social attention in typically developing human and nonhuman primate infants. We examined the normative development of attention to dynamic social and nonsocial stimuli longitudinally in macaques (Macaca mulatta) at 1, 3, and 5 months of age (N = 75) and humans at 2, 4, 6, 8, and 13 months of age (N = 69) using eye tracking. All infants viewed concurrently played silent videos—one social video and one nonsocial video. Both macaque and human infants were faster to look to the social than the nonsocial stimulus, and both species grew faster to orient to the social stimulus with age. Further, macaque infants’ social attention increased linearly from 1 to 5 months. In contrast, human infants displayed a nonlinear pattern of social interest, with initially greater attention to the social stimulus, followed by a period of greater interest in the nonsocial stimulus, and then a rise in social interest from 6 to 13 months. Overall, human infants looked longer than macaque infants, suggesting humans have more sustained attention in the first year of life. These findings highlight potential species similarities and differences, and reflect a first step in establishing baseline patterns of early social attention development.     

Increased rate of parental postpartum depression and traumatization in moderate and late preterm infants is independent of the infant's motor repertoire

Background

Moderately and late preterm infants represent a considerable and increasing proportion of infants cared for in neonatal departments worldwide. Parents of preterm infants are at risk of postpartal depression (PPD) and posttraumatic stress disorder (PTSD), and preterm infants are at risk of developmental impairment.

Aim

This study aimed to assess (1) the incidence of parental PPD and PTSD in moderate to late preterm infants in comparison to full-term infants and (2) the influence of infants' motor repertoire assessed by Prechtl's general movements and illness severity on parental PPD and PTSD.

Subjects

We studied 60 mothers and 56 fathers of 69 preterm infants (born at 32 to 37 weeks of gestation) and 32 mothers and 29 fathers of 34 full-term infants.

Outcome measures

We assessed the incidence of parental PPD, PTSD and perceived social support as well as infants' illness severity and motor repertoire at birth, term and 3 months corrected age.

Results

Preterm mothers and fathers had significant higher depression scores after birth compared to full-term parents (p = 0.033 and 0.021). Preterm fathers also had higher traumatization scores compared to full-term fathers (p = 0.007). Probable or possible PPD/PTSD was not associated with infant's illness severity or quality of motor repertoire. No differences in motor development were found between preterm and full-term infants.

Conclusion

Moderate to late preterm infants' parents are at increased risk for PPD irrespective of infants' motor repertoire or illness severity.     

Telomerase activity analyzed with TRAP in situ provides additional information in effusions remaining equivocal after immunocytochemistry and hyaluronan analysis

Cytology is central in the diagnosis of malignancy in effusions. Ancillary techniques, mainly immunocytochemistry, have considerably improved the sensitivity but some 10% of all cases remain equivocal and require the addition of new diagnostic modalities. We have previously shown that strong nuclear telomerase activity determined with Telomere Repeat Amplification Protocol (TRAP) in situ is specific for malignant cells and could be a candidate for an additional test. Thirty effusions remaining diagnostically equivocal after the use of immunocytochemistry and the determination of the hyaluronan content were reviewed and their TRAP in situ reactivity was related to the definitive diagnoses based on all available data. There were seven effusions from patients with definitive benign diagnoses and 23 effusions from patients with definitive malignant diagnoses. Strong telomerase activity was seen only in effusions from patients with definitive malignant diagnosis, all effusions from patients with benign disease lacking strong telomerase activity, whereas eight of the malignant cases, including three cases of epithelial mesothelioma, showed strong reactivity. Strong nuclear TRAP in situ reactivity was demonstrated only in effusions from patients with verified malignant disease. Although the study is small, it suggests that TRAP in situ activity provides diagnostic information in about one‐third of effusions remaining cytologically equivocal after the use of current ancillary techniques. The most striking diagnostic improvement appears to be gained in epithelial mesotheliomas. Diagn. Cytopathol. 2014;42:1051–1057. © 2014 Wiley Periodicals, Inc.     

Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis

Objective. To analyze whether the intestinal mucosa in rheumatoid arthritis (RA) is immnunologically abnormal and whether sulfasalazine (SSZ) possesses any local intestinal immunoregulatory effect. Methods. Lymphocyte subpopulations and HLA—DR expression were evaluated in biopsy specimens from the duodenal—jejunal mucosa and in peripheral blood samples obtained from 17 patients with RA, both before and after 16 weeks of SSZ treatment. The same mucosal assays were also performed in 7 controls. Results. The mucosa of the small intestine in RA patients showed no differences in morphology, HLA—DR expression, or the amounts and distribution of CD3+, CD4+, CD8+, and γ/δ+ lymphocytes compared with the control group. However, there was a reduction in mucosal CD3+ and γ/δ+ lymphocyte numbers after SSZ therapy, which did not correspond to a change in peripheral blood CD3+ lymphocyte number. SSZ treatment also tended to diminish the peripheral blood CD4+:CD8+ cell ratio (P = 0.05). Conclusion. No signs of inflammation or immunologic abnormalities were seen in RA duodenal-jejunal mucosa. In this part of the intestine, however, SSZ exerted immunoregulatory effects that were not encountered in the peripheral blood.