Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58

A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II-matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58

Bone Mineral Density in Transgender Individuals After Gonadectomy and Long-Term Gender-Affirming Hormonal Treatment

Introduction: Establishing the influence of long-term, gender-affirming hormonal treatment (HT) on bone mineral density (BMD) in transgender individuals is important to improve the therapeutic guidelines for these individuals. Aim: To examine the effect of long-term HT and gonadectomy on BMD in transgender individuals. Methods: 68 transwomen and 43 transmen treated with HT who had undergone gonadectomy participated in this study. Dual-energy x-ray absorptiometry (DXA) scans were performed to measure BMD at the lumbar spine and total hip. Laboratory values related to sex hormones were collected within 3 months of performing the DXA scan and analyzed. Main Outcome Measure: BMD and levels of sex hormones in transwomen and transmen. Results: In transwomen, the mean BMD values at the lumbar spine and total hip at the first DXA scan were, respectively, 0.99 ± 0.15 g/cm2 (n = 68) and 0.94 ± 0.28 g/cm2 (n = 65). In transmen, the mean BMD values at the lumbar spine and total hip at the first DXA scan were, respectively, 1.08 ± 0.16 g/cm2 (n = 43) and 1.01 ± 0.18 g/cm2 (n = 43). A significant decrease in total hip BMD was found in both transwomen and transmen after 15 years of HT compared with 10 years of HT (P =.02). Conclusion: In both transwomen and transmen, a decrease was observed in total hip bone mineral density after 15 years of HT compared to the first 10 years of HT. Dobrolińska M, van der Tuuk K, Vink P, et al. Bone Mineral Density in Transgender Individuals After Gonadectomy and Long-Term Gender-Affirming Hormonal Treatment. J Sex Med 2019; 16:1469–1477

Chronic granulomatous disease: the European experience.

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

CRISPR/Cas9 screen for genome-wide interrogation of essential MYC-bound E-boxes in cancer cells

The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines - K562, ST486, HepG2 and MCF7 - which revealed several essential E-boxes and genes. Among them we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.</p

The relationship between natural outdoor environments and cognitive functioning and its mediators

Background Urban residents may experience cognitive fatigue and little opportunity for mental restoration due to a lack of access to nature. Natural outdoor environments (NOE) are thought to be beneficial for cognitive functioning, but underlying mechanisms are not clear. Objectives To investigate the long-term association between NOE and cognitive function, and its potential mediators. Methods This cross-sectional study was based on adult participants of the Positive Health Effects of the Natural Outdoor Environment in Typical Populations in Different Regions in Europe (PHENOTYPE) project. Data were collected in Barcelona, Spain; Doetinchem, the Netherlands; and Stoke-on-Trent, United Kingdom. We assessed residential distance to NOE, residential surrounding greenness, perceived amount of neighborhood NOE, and engagement with NOE. Cognitive function was assessed with the Color Trails Test (CTT). Mediation analysis was undertaken following Baron and Kenny. Results Each 100 m increase in residential distance to NOE was associated with a longer CTT completion time of 1.50% (95% CI 0.13, 2.89). No associations were found for other NOE indicators and cognitive function. Neighborhood social cohesion was (marginally) significantly associated with both residential distance to NOE and CTT completion time, but no evidence for mediation was found. Nor were there indications for mediation by physical activity, social interaction with neighbors, loneliness, mental health, air pollution worries, or noise annoyance. Conclusions Our findings provide some indication that proximity to nature may benefit cognitive function. We could not establish which mechanisms may explain this relationship