PUM1 Mediates the Posttranscriptional Regulation of Human Fetal Hemoglobin

The fetal-to-adult hemoglobin switching at about the time of birth involves a shift in expression from γ-globin to β-globin in erythroid cells. Effective re-expression of fetal γ-globin can ameliorate sickle cell anemia and β-thalassemia. Despite the physiological and clinical relevance of this switch, its posttranscriptional regulation is poorly understood. Here, we identify Pumilo 1 (PUM1), an RNA-binding protein with no previously reported functions in erythropoiesis, as a direct posttranscriptional regulator of β-globin switching. PUM1, whose expression is regulated by the erythroid master transcription factor erythroid Krüppel-like factor (EKLF/KLF1), peaks during erythroid differentiation, binds γ-globin messenger RNA (mRNA), and reduces γ-globin (HBG1) mRNA stability and translational efficiency, which culminates in reduced γ-globin protein levels. Knockdown of PUM1 leads to a robust increase in fetal hemoglobin (∼22% HbF) without affecting β-globin levels in human erythroid cells. Importantly, targeting PUM1 does not limit the progression of erythropoiesis, which provides a potentially safe and effective treatment strategy for sickle cell anemia and β-thalassemia. In support of this idea, we report elevated levels of HbF in the absence of anemia in an individual with a novel heterozygous PUM1 mutation in the RNA-binding domain (p.(His1090Profs∗16); c.3267_3270delTCAC), which suggests that PUM1-mediated posttranscriptional regulation is a critical player during human hemoglobin switching

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

A spill over effect of entrepreneurial orientation on technological innovativeness:an outlook of universities and research based spin offs

partially_open5siBy shifting towards Romer’s (Am Econ Rev 94:1002–1037, 1986) economy and so the spread of knowledge economy, universities started to adopt a collaborative approach with their entrepreneurial ecosystem. They turn out to be risk taker, autonomous, proactive, competitive, and innovative. In a nutshell, they are entrepreneurial oriented with the aim to generate new innovative ventures, known as research-based spin offs. Doubly, this has induced an improvement of technology transfer and the degree of entrepreneurship in the current knowledge economy. However there still is a paucity of studies on the spill over effect of entrepreneurial orientated universities and research-based spin off on technology transfer need to be more explored. Therefore, the article investigates the link between entrepreneurial orientation and such spill overs by offering an outlook of two universities and two research-based spin offs in the United Kingdom. The scope is to provide a deep view of technological innovativeness in a research context, entrepreneurial oriented. Our research suggests that entrepreneurial attitude has become an imperative to succeed in the context where British institutions currently operate. Entrepreneurship brings the necessary technological innovation to the university and its students, which results in better positioning of the university at national and international levels, with the subsequent impact on their ability to attract not only new students and academics but also funding to conduct their research.openScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, FrancescoScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, Francesc

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Relationship between androgen biosynthesis linked to 3βHSD1 and resistance to radiotherapy: A germline biomarker for combined androgen blockade with radiation in high-risk prostate cancer

e17084 Background: Around 50% of men with advanced prostate cancer (PCa) have at least one germline copy of the adrenal-permissive (1245C) HSD3B1 allele. This allele leads to higher levels of the steroid biosynthesis enzyme, 3β-hydroxysteroid dehydrogenase (3βHSD1). Inheriting this allele is linked to worse outcomes in men with advanced PCa. To determine if (1245C) HSD3B1 could be causing early resistance to combined androgen deprivation and radiotherapy in localized PCa, we studied its role in modulating radioresistance. Methods: PCa cell lines were used to investigate the reciprocal effects of 3βHSD1 knockdown and overexpression in intrinsically high and low 3βHSD1 lines, respectively. PCa xenografts were used to confirm the results in vivo. The connection between androgen receptor (AR) expression and elevated DNA Damage Response (DDR) gene expression was validated using transcriptomic data from 680 radical prostatectomy specimens The ability of enzalutamide, a non-steroidal anti-androgen, to restore radiosensitivity in 1245C expressing lines was interrogated in vitro and in vivo. Results: 1245C HSD3B1 expressing PCa lines displayed increased clonogenic survival after ionizing radiation. Effects were dependent on the 3βHSD1 substrate, DHEA, confirming intratumoral androgen metabolism was required for radioresistance. Resistant lines showed enhanced DNA double-strand break (DSB) repair and heightened DDR gene expression. PCa xenografts with 1245C HSD3B1 were similarly more resistant to radiation using murine models that faithfully mimic human adrenal physiology. A correlation between AR expression and increased DDR gene expression was confirmed in 680 patient samples. Enzalutamide pretreatment resulted in a decrease in DSB repair ability and re-sensitized 1245C HSD3B1 PCa cells to radiation. Conclusions: 1245C HSD3B1 fuels prostate cancer treatment resistance by elevating regional androgen biosynthesis from adrenal steroid precursors, leading to DDR gene overexpression and enhanced DNA DSB repair kinetics. This work supports clinical validation of biomarker informed selective intensification strategies, e.g., combined androgen blockade, for high-risk men with the 1245C HSD3B1 allele receiving curative intent radiotherapy