Inactivation of p16 INK4a /CDKN2A gene may be a diagnostic feature of large B cell lymphoma leg type among cutaneous B cell lymphomas

The World Health Organization-European Organization for Research and Treatment of Cancer has individualized three main categories among the primary cutaneous B cell lymphoma (PCBCL): leg-type primary cutaneous large B cell lymphoma (PCLBCL leg type), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous marginal zone lymphoma (PCMZL). The genetic features of 21 PCBCL cases (six PCLBCL leg type four PCFCL large cells, seven PCFCL small cells, and four PCMZL) were investigated by comparative genomic hybridization (CGH array). Fluorescent in situ hybridization (FISH) analysis was performed to confirm CGH array data and to detect lymphoma-associated gene rearrangements. p14 ( ARF )/p16 ( INK4a ) CDKN2A gene quantification, methylation analysis, and immunohistochemical detection were also performed. CGH array showed a higher number of recurrent genetic imbalances in PCLBCL leg type (mean 62) than in PCFCL large cells (mean 34). PCFCL small cells and PCMZL exhibited fewer chromosomal alterations (mean 24 and 9). FISH analysis provided concordant results with CGH array data in 97% (98 of 101) assays and demonstrated a t(8;14)(q24;q32) in two of six PCLBCL leg type. Recurrent deletions in 9p21 (p14 ( ARF )/p16 ( INK4a ) CDKN2A) were a constant finding in PCLBCL leg type (six of six). Conversely, PCFCL large cells exhibited recurrent 1p36 deletions (four of four) without deletion in 9p21 (zero of four). The diagnostic and prognostic impact of the p16 ( INK4a ) CDKN2A gene status in PCBCL should therefore be confirmed on a larger series.     

Antagonism of protease-activated receptor 2 protects against experimental colitis

Many trypsin-like serine proteases such as β-tryptase are involved in the pathogenesis of colitis and inflammatory bowel diseases. Inhibitors of individual proteases show limited efficacy in treating such conditions, but also probably disrupt digestive and defensive functions of proteases. Here, we investigate whether masking their common target, protease-activated receptor 2 (PAR2), is an effective therapeutic strategy for treating acute and chronic experimental colitis in rats. A novel PAR2 antagonist (5-isoxazoyl-Cha-Ile-spiro[indene-1,4'-piperidine]; GB88) was evaluated for the blockade of intracellular calcium release in colonocytes and anti-inflammatory activity in acute (PAR2 agonist-induced) versus chronic [2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced] models of colitis in Wistar rats. Disease progression (disease activity index, weight loss, and mortality) and postmortem colonic histopathology (inflammation, bowel wall thickness, and myeloperoxidase) were measured. PAR2 and tryptase colocalization were investigated by using immunohistochemistry. GB88 was a more potent antagonist of PAR2 activation in colonocytes than another reported compound, N1-3-methylbutyryl-N?-6-aminohexanoyl-piperazine (ENMD-1068) (IC?? 8 μM versus 5 mM). Acute colonic inflammation induced in rats by the PAR2 agonist SLIGRL-NH? was inhibited by oral administration of GB88 (10 mg/kg) with markedly reduced edema, mucin depletion, PAR2 receptor internalization, and mastocytosis. Chronic TNBS-induced colitis in rats was ameliorated by GB88 (10 mg/kg/day p.o.), which reduced mortality and pathology (including colon obstruction, ulceration, wall thickness, and myeloperoxidase release) more effectively than the clinically used drug sulfasalazine (100 mg/kg/day p.o.). These disease-modifying properties for the PAR2 antagonist in both acute and chronic experimental colitis strongly support a pathogenic role for PAR2 and PAR2-activating proteases and therapeutic potential for PAR2 antagonism in inflammatory diseases of the colon.     

School travel planning: mobilizing school and community resources to encourage active school transportation

BACKGROUND: Active school transport (AST), school travel using an active mode like walking, may be important to children's overall physical activity. A “school travel plan” (STP) documents a school's transport characteristics and provides an action plan to address school and neighborhood barriers to AST. METHODS: We conducted a pilot STP intervention at 12 schools in 4 Canadian provinces. Facilitators and school personnel created and implemented AST action plans. Parent's self‐reports (N = 1489) were the basis for evaluating the intervention. A content analysis identified type, frequency, and perceived success of initiatives. RESULTS: School travel plans emphasized education and promotion, and AST activities and events. Capital improvement projects were more common at schools in older suburban neighborhoods, whereas enforcement was more common at schools in newer suburban neighborhoods. Rates of active transportation increased from 43.8% to 45.9%. At follow‐up, 13.3% of households reported less driving. Parents/caregivers cited weather, convenience, and trip chaining as primary reasons for continued driving. CONCLUSION: The STP process may facilitate changes to patterns of school travel. An STP can expand a school's capacity to address transportation issues through mobilization of diverse community resources. Future STP initiatives may benefit from addressing convenience, safety through enforcement, and by examining how schools can be supported in implementing infrastructure improvements.     

Neuronal Programmed Cell Death-1 Ligand Expression Regulates Retinal Ganglion Cell Number in Neonatal and Adult Mice

OBJECTIVES:: During mouse retina maturation, the final number of retinal ganglion cells (RGCs) is determined by highly regulated programmed cell death. Previous studies demonstrated that the immunoregulatory receptor programmed cell death-1 (PD-1) promotes developmental RGC death. To identify the functional signaling partner(s) for PD-1, we identified retinal expression of PD-1 ligands and examined the effect of PD-1 ligand expression on RGC number. We also explored the hypothesis that PD-1 signaling promotes the development of functional visual circuitry. METHODS:: Characterization of retinal and brain programmed cell death-1 ligand 1 (PD-L1) expression were examined by immunofluorescence on tissue sections. The contribution of PD-ligands, PD-L1, and programmed cell death-1 ligand 2 (PD-L2) to RGC number was examined in PD-ligand knockout mice lacking 1 or both ligands. Retinal architecture was assessed by spectral-domain optical coherence tomography, and retinal function was analyzed by electroretinography in wild-type and PD-L1/L2 double-deficient mice. RESULTS:: PD-L1 expression is found throughout the neonatal retina and persists in adult RGCs, bipolar interneurons, and Müller glia. In the absence of both PD-ligands, there is a significant numerical increase in RGCs (34% at postnatal day 2 [P2] and 18% in adult), as compared to wild type, and PD-ligands have redundant function in this process. Despite the increased RGC number, adult PD-L1/L2 double-knockout mice have normal retinal architecture and outer retina function. CONCLUSION:: This study demonstrates that PD-L1 and PD-L2 together impact the final number of RGCs in adult mice and supports a novel role for active promotion of neuronal cell death through PD-1 receptor-ligand engagement.     

Can MRI differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma? A systematic review

Background and purpose — Adequate staging of chondroid tumors at diagnosis is important as it determines both treatment and outcome. This systematic review provides an overview of MRI criteria used to differentiate between atypical cartilaginous tumors (ACT) and high-grade chondrosarcoma (HGCS).Patients and methods — For this systematic review PubMed and Embase were searched, from inception of the databases to July 12, 2018. All original articles describing MRI characteristics of pathologically proven primary central chondrosarcoma and ACT were included. A quality appraisal of the included papers was performed. Data on MRI characteristics and histological grade were extracted by 2 reviewers. Meta-analysis was performed if possible. The study is registered with PROSPERO, CRD42018067959.Results — Our search identified 2,132 unique records, of which 14 studies were included. 239 ACT and 140 HGCS were identified. The quality assessment showed great variability in consensus criteria used for both pathologic and radiologic diagnosis. Due to substantial heterogeneity we refrained from pooling the results in a meta-analysis and reported non-statistical syntheses. Loss of entrapped fatty marrow, cortical breakthrough, and extraosseous soft tissue expansion appeared to be present more often in HGCS compared with ACT.Interpretation — This systematic review provides an overview of MRI characteristics used to differentiate between ACT and HGCS. Future studies are needed to develop and assess more reliable imaging methods and/or features to differentiate ACT from HGCS.

The incidence of chondrosarcoma of bone appears to have been increasing during the last decade and is now reported to be the most common primary malignant bone tumor in several countries (Thorkildsen et al. 2018, van Praag et al. 2018). Conventional chondrosarcoma is the most common subtype of chondrosarcoma. Other subtypes of chondrosarcoma (e.g., juxtacortical, mesenchymal, or secondary chondrosarcoma) are rare and show different radiologic appearance and clinical behavior (Bindiganavile et al. 2015).Conventional chondrosarcoma is classified into the histological grades 1 (currently known as atypical cartilaginous tumor [ACT]), 2, and 3. The metastatic potential, and therefore the disease-specific survival, correlates with the histological grade (Fletcher et al. 2013, Laitinen et al. 2018, Thorkildsen et al. 2018). ACTs rarely metastasize and are therefore reclassified as an intermediate type of tumor, not a malignancy (Fletcher et al. 2013). Due to the increase in patients undergoing MRI examinations for joint-related complaints, the incidental detection of ACT has increased substantially (van Praag et al. 2018).With the increasing incidence of ACT, clear radiologic criteria to differentiate ACT from high-grade chondrosarcoma (i.e., grades 2 and 3) become more and more important. Adequate staging of chondroid tumors at diagnosis is important as it determines both treatment and prognosis. High-grade chondrosarcomas behave aggressively. Between 10% and 30% of grade 2 and about 70% of grade 3 chondrosarcomas metastasize (Evans et al. 1977). Hence, high-grade chondrosarcoma (HGCS) requires wide en bloc resection with free surgical margins. In contrast, ACTs are intermediate tumors and can be treated either with intralesional curettage and local adjuvant or nonoperatively with regular follow-up when located in the long bones (Deckers et al. 2016).Due to the heterogenous composition of chondroid tumors, diagnostic biopsy is unreliable in assessing the genuine histological grade and malignant potential of chondrosarcomas (Laitinen et al. 2018). Therefore, physicians need to rely on imaging and clinical findings (e.g., pain is more common in HGCS) to differentiate ACT from HGCS. Imaging evaluation of cartilaginous and other bone tumors is generally based on multimodal assessment including at least conventional radiography and MRI (Nascimento et al. 2014).During the most recent decades research has focused mainly on differentiating enchondroma from chondrosarcoma (Choi et al. 2013, Douis et al. 2014, Crim et al. 2015, Lisson et al. 2018). New insights have shown that both enchondroma and ACT located in the long bones can be observed without treatment (Deckers et al. 2016, Sampath Kumar et al. 2016, Chung et al. 2018). These insights make the differentiation between ACT and HGCS clinically relevant. Currently, literature on differentiating ACT from HGCS is sparse and clear radiologic criteria are lacking. Therefore, we performed a systematic review to provide an overview of MRI characteristics used to date to differentiate between ACT and HGCS.     

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin and LEAP2, in a 4‐day binge eating model

The growth hormone secretagogue receptor (GHSR) is a G protein‐coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver‐expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin‐evoked activity. GHSR also displays ligand‐independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake‐related behaviours, including binge eating. Previously, we reported that GHSR‐deficient mice daily and time‐limited exposed to a high‐fat (HF) diet display an attenuated binge‐like HF intake compared to wild‐type mice. In the present study, we aimed to determine whether ligand‐independent GHSR activity affects binge‐like HF intake in a 4‐day binge‐like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge‐like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K‐(D‐1‐Nal)‐FwLL‐NH₂, which are both blockers of constitutive GHSR activity, reduced binge‐like HF intake, whereas central administration of ghrelin or the ghrelin‐evoked GHSR activity blockers [D‐Lys3]‐GHRP‐6 and JMV2959 did not modify binge‐like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge‐like HF intake in mice independently of plasma levels of ghrelin and LEAP2.     

Chromosomal imbalances: a hallmark of tumour relapse in primary cutaneous CD30+ T-cell lymphoma

Primary cutaneous CD30+ large T-cell lymphoma (CD30+ CTCL) is a subset of non-epidermotropic primary cutaneous T-cell lymphoma. Although frequent spontaneous regression may be observed, skin relapses occur frequently. Cytogenetic abnormalities that could play a role in CD30+ CTCL tumour pathogenesis and relapses remain unknown. The identification of recurrent cytogenetic abnormalities is hampered by difficulty in culturing tumours and the lack of CD30+ CTCL serial studies comparing genetic changes both at diagnosis and at relapse. The purpose of this study was to investigate the cytogenetic abnormalities present in a series of 13 CD30+ CTCL samples obtained from nine patients fulfilling both EORTC and WHO diagnostic criteria, by the use of comparative genomic hybridization (CGH). CGH analysis revealed a non-random distribution of genetic imbalances between relapsing and non-relapsing disease. In relapsing disease, chromosomal abnormalities were detected both in the primary tumour and in relapses. The mean number of changes in non-relapsing disease was 0.33 (range 0-1), compared with 6.29 (range 1-16) in relapsing disease. The recurrent chromosomes involved in relapsing disease were chromosomes 6 (86%), 9 (86%), and 18 (43%). While chromosome 9 was mostly affected by gain, chromosomes 6 and 18 mainly contained regions of loss, exclusively on 6q and 18p. The common regions of deletion were 6q21 and 18p11.3. In one patient, we successfully cultured tumour cells from a skin biopsy from a second relapse. The G-banded karyotype was concordant with both CGH and fluorescence in situ hybridization (FISH) results. Although further studies are required to strengthen these data, this CGH analysis demonstrates chromosomal imbalances that may be involved in the pathogenesis of relapsing CD30+ CTCL.     

Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes

The following guidelines were adopted by an Ad Hoc Committee convened at the Fourth International Workshop on the Fragile X Syndrome and X-Linked Mental Retardation to establish minimum cytogenetic standards for the preparation and analysis of the fragile X chromosome. The intention of the committee was to develop and provide practical standards for the routine cytogenetic detection of the fragile X. The guidelines describe reasonable criteria for effective tissue culture methods for eliciting the Xq27.3 fragile site in vitro and for the analysis of such chromosome preparations.