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We test the hypothesis that internal waves observed in flow over forest canopies are generated by Kelvin–Helmholtz instability. The waves were observed at night, under stably stratified and weak wind conditions, with a horizontally scanning aerosol lidar and an instrumented tower. The lidar images are used to determine the salient wavelength and phase propagation velocity of each episode. Time series data measured at the tower are then used to form vertical profiles of background velocity and buoyancy just before each observed wave event. The profiles are input to the Taylor–Goldstein equation to predict the phase velocity, wavelength and period of the fastest-growing linear instability, and the results compared with the lidar observations. The observed wavelengths tend to be longer than predicted by the Taylor–Goldstein theory, typically by a factor of two. That discrepancy is removed when the theory is extended to account for the effects of ambient, small-scale turbulence.

In the metallic components fabricated by the emerging selective laser melting (SLM) technology, most strategies used for strengthening the materials sacrifice the ductility, leading to the so-called strength-ductility trade-off. In the present study, we report that the strength and ductility of materials can be enhanced simultaneously by introducing nanoparticles, which can break the trade-off of the metallic materials. In the case of in-situ nano-TiB2 decorated AlSi10Mg composites, the introduced nanoparticles lead to columnar-to-equiaxed transition, grain refinement and texture elimination. With increasing content of nanoparticles, the strength increases continually. Significantly, the ductility first increases and then decreases. Our results show that the ductility is controlled by the competition between the crack-induced catastrophic fracture and ductile fracture associated with dislocation activities. The first increase of ductility is mainly attributed to the suppression of crack-induced catastrophic fracture when TiB2 nanoparticles present. With the further increase of TiB2 nanoparticles, the subsequent decrease of ductility is mainly controlled by dislocation activities. Thus, the materials will exhibit the optimum strength and ductility combination in a certain range of TiB2 nanoparticles. This study clarifies the physical mechanism controlling ductility for nano-TiB2 decorated AlSi10Mg composites, which provides the insights for the design of structural materials.

BackgroundThis study aimed to determine to what extent an aging population and shift to chronic illness has contributed to emergency admissions at a tertiary care hospital over ten years.MethodsThis was a retrospective observational study performed using a database of all emergency admissions from the Emergency Department (ED) at a single tertiary hospital in Singapore during a ten-year period (January 1st, 2008 to December 31st, 2017). Emergency admissions were defined as ED visits with inpatient admission as the disposition. This study analyzed the trends of demographics, pre-existing comorbidities, chronic conditions or ambulatory care sensitive conditions (ACSC) of all patients who underwent emergency admissions in Singapore General Hospital.ResultsA total of 446,484 emergency records were included. For elderly patients, the proportions of them had pre-existing multimorbidity at the time of undergoing emergency admissions were found to be lower at the end the 10-year study period relative to the beginning of the study period. The proportions of emergency admissions whose ED primary diagnoses were categorized as chronic conditions and certain chronic ACSC including chronic obstructive pulmonary disease, congestive heart failure, diabetes complications, and epilepsy also decreased for elderly patients over the 10-year study period.ConclusionsIn Singapore, despite a rapidly aging population, there have been surprisingly lower proportions of chronic conditions, pre-existing comorbidities, and chronic ACSC among the elderly emergency admissions. This is possibly consistent with an overall improved management of the chronic conditions among the elderly population. Future studies should include similar studies at the national level and comparison with other healthcare settings in different countries.

Background Cardiac rehabilitation is a class IA recommendation for patients with cardiovascular diseases. Physical activity is the core component and core competency of cardiac rehabilitation programs. Cardiac rehabilitation guidelines recommend patients achieve at least thirty minutes of moderate-to-vigorous intensity physical activity five or more days per week. However many patients with cardiovascular diseases are failing to meet recommended daily physical activity levels. eHealth interventions may increase moderate-to-vigorous intensity physical activity among cardiac rehabilitation participants. Objectives The objective of this study was to review the evidence of the effectiveness of eHealth interventions to increase moderate-to-vigorous intensity physical activity among cardiac rehabilitation participants. The secondary objective was to examine the effectiveness of eHealth interventions on improving exercise capacity, cardiovascular risk profile and health-related quality of life. Methods A comprehensive search strategy was developed for four electronic databases (PubMed, Web of Science, Embase and The Cochrane Library); through December 16, 2021. All studies reporting on eHealth interventions designed to increase moderate-to-vigorous physical activity among cardiac rehabilitation participants were included. Multiple not-blind reviewers determined study eligibility and extracted data. Risk of bias was evaluated using the Cochrane Collaboration Tool for randomized controlled trials and using the Effective Practice and Organisation of Care Cochrane Review Group for non-randomized controlled trials. Data quality using the Grading of Recommendations Assessment, Development and Evaluation professional guideline development tool. Data were pooled using a random-effects model. All statistical analyses were performed using Stata 17. Results Twenty-one studies were included in the review which fifteen were in the meta-analysis. The meta-analysis demonstrated eHealth interventions improved moderate-to-vigorous physical activity (standard mean difference = 0.17, 95% confidence interval: 0.07, 0.27, P Conclusions eHealth interventions are effective at increasing minutes/week of moderate-to-vigorous intensity physical activity among cardiac rehabilitation participants. Future high-quality empirical studies are needed to evaluate the effectiveness of eHealth interventions delivered, with these sub-types (wearable devices, online web portal, smart phone application, messaging services and telephone calls) delivered alone or in combination delivered more conducive to moderate-to-high intensity physical activity. Funding Acknowledgement Type of funding sources: None.

STUDY QUESTIONWhat is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them?SUMMARY ANSWERThe GATA-1/CREB1/WNT signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes.WHAT IS KNOWN ALREADYrIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM.STUDY DESIGN, SIZE, DURATIONWe applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid.PARTICIPANTS/MATERIALS, SETTING, METHODSHuman oocytes were collected from donors aged 28–41 years with a body mass index of MAIN RESULTS AND THE ROLE OF CHANCEThe transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P LARGE SCALE DATARaw data from this study can be accessed through GSE158539.LIMITATIONS, REASONS FOR CAUTIONIn the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator.WIDER IMPLICATIONS OF THE FINDINGSThis study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare.

Introduction: Foreign workers (FWs) on work permit face unique health challenges and potential barriers to healthcare. We aimed to examine the epidemiology, attendance patterns, disposition, and adherence to follow-up, by FWs on work permit to two emergency departments (EDs) in Singapore. Methods: In this retrospective observational study, we included consecutive FWs on work permit who registered at the EDs of two public restructured hospitals from 1 May 2016 to 31 October 2016. Data obtained from electronic medical records included patient demographics, triage acuity, disposition, ED diagnoses and bill information. Results: There were 6,429 individual FWs on work permit who contributed to 7,157 ED visits over the 6-month study period, with male predominance (72.7%, 4672/6429), and median age of 31 (interquartile range 26 to 38) years. A high proportion of these FWs were triaged to low-acuity status compared to the general ED population (66.9% versus 45.9%, P

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.

Background Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. Methods We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. Results Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bβ and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bβ I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. Conclusions Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.

Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell–derived macrophages, and in murine bone marrow–derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition. Refereed/Peer-reviewed

Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient‐derived cell cultures (PDCs) from chemo‐naïve and post–treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo‐response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal‐type gene expression signature and showed upregulation of pro‐angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard‐of‐care cytotoxics at human C max‐equivalent concentrations, MYCN‐amplified and non‐MYCN‐amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients’ responses, and correlated with gene signatures of chemosensitivity. In this translational proof‐of‐concept study, early‐phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug‐response testing., We developed a system to efficiently and consistently generate patient‐derived cultures (PDCs) of neuroblastoma that recapitulated individual patient’s cytogenetic and immunohistochemical features, and phenotypic responses to standard‐of‐care chemotherapy. PDCs predominantly express the gene signature of the recently described neuroblastoma mesenchymal super‐enhancer state. This proof‐of concept provides translational evidence supporting the proposed role of the mesenchymal cell subpopulation in determining clinical treatment response and offers a novel platform for developing personalized ex vivo therapeutic decision‐making strategies for neuroblastoma.

International audience; Selective laser melting (SLM) of aluminium alloys is of research interest to produce customized or complexshaped metal components for functional or structural applications. In order to palliate the undesirable residual stress developed in the SLM process, traditional post-annealing heat treatment has been widely used to lower residual stress in selective laser melted (SLMed) Al alloys. However, the traditional post-annealing method usually leads to a decrease in strength which is another concern for applications. In this study, we developed and validated a new strategy combining post-uphill quenching and subsequent ageing to simultaneously minimise residual stress and increase the strength of SLMed nano-TiB2 decorated Al alloy parts. The results show that the high as-built residual stress was partly counteracted by the newly-produced residual stress in the opposite direction during the uphill quenching stage and synergistically reduced by dislocation recovery during the ageing stage. The microstructural features of grains and cell structures remain unchanged after the treatment. While substantial new nano-Si particles with dot-like or needle-like morphology precipitate inside the cells. The tensile strength was improved mainly due to effective precipitation strengthening by dispersed nanosized Si precipitates. The proposed strategy is expected to be useful in other materials and components fabricated by SLM in which residual stress is also unwanted.

Mitogen-activated protein kinase (MAPK) pathway plays a major role in pediatric low-grade gliomas (pLGGs). Immunohistochemistry with mutant-specific antibody, VE1, has appeared to be the most affordable and rapidly deployable method to identify tumors with aberrant MAPK signaling pathway, by highlighting tumor with BRAFV600E mutation. Nonetheless, positive staining cases but not associated with BRAFV600E mutation are also seen. We analyzed 62 pLGGs for the two commonest genetic aberrations in MAPK pathway: KIAA1549-BRAF fusion, using reverse-transcriptase polymerase chain reaction, and BRAFV600E mutation, using VE1 antibody and Sanger sequencing. We recorded a specificity and accuracy rate of 68.75% and 75%, respectively, for VE1, when strong cytoplasmic staining is observed. Interestingly, we observed that cells with ganglionic features frequently bind VE1 but not associated with BRAFV600E mutation. Such observation was also confirmed in four cases of differentiating neuroblastoma. This false positive staining may serve as an important confounder in the interpretation of VE1 immunoreactivity with major therapeutic implication. It is important to confirm the presence of BRAFV600E mutation by DNA-based method, especially in tumor entities not known to, or rarely harbor such mutations.

We report the first case of an ovarian pericytoma with t(7;12). An 11-year-old child presented with abdominal pain and distension. A suprapubic mass was detected on examination and radiological investigations revealed a 16.5 cm solid-cystic ovarian mass. Histologically, the tumor was composed of spindle cells with S100-protein, Bcl-2, and CD10 reactivity on immunohistochemistry. Alpha fetoprotein, calretinin, alpha-inhibin, WT1, smooth muscle actin, caldesmon, desmin, cytokeratins, chromogranin, synaptophysin, EMA, Sox10, CD117, CD31, CD34, and CD68 were all negative. Molecular tests showed t(7;12)(p22;q13), resulting in the fusion of the ACTB with GLI1 genes and a diagnosis of pericytoma with t(7;12) of the ovary was made. We discuss the difficulties in diagnosing this lesion in the ovary and highlight the importance on molecular tests in characterizing challenging cases, especially primary ovarian spindle cell mesenchymal tumors.

Background Primary paediatric epidural sarcomas are extremely rare. Overall, there remains a paucity of knowledge in paediatric epidural sarcomas owing to the infrequent number of cases. The Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) is a next-generation sequencing assay that has been reported to be a useful technique to detect recurrent fusion in sarcomas. We report the molecular exploration of 3 primary paediatric epidural sarcomas—one in the cranium (mesenchymal chondrosarcoma) and 2 in the spine (mesenchymal chondrosarcoma and Ewing sarcoma respectively). Case presentation This is a study approved by the hospital ethics board. Clinico-pathological information from 3 consenting patients with primary epidural sarcomas was collected. These selected tumours are interrogated via Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) for genomic aberrations. Results were validated with RT-PCR and Sanger sequencing. All findings are corroborated and discussed in concordance with current literature. Our findings show 2 variants of the HEY1-NCOA2 gene fusion: HEY1 (exon 4)-NCOA2 (exon 13) and HEY1 (exon 4)-NCOA2 (exon 14), in both mesenchymal chondrosarcoma patients. Next, the Ewing sarcoma tumour is found to have EWSR1 (exon 10)-FLI1 (exon 8) translocation based on NGS. This result is not detected via conventional fluorescence in situ testing. Conclusions This is a molecularly-centered study based on 3 unique primary paediatric epidural sarcomas. Our findings to add to the growing body of literature for these exceptionally rare and malignant neoplasms. The authors advocate global collaborative efforts and in-depth studies for targeted therapy to benefit affected children.

Importance Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab’s performance. Objective To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design, Setting, and Participants A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers. Main Outcomes and Measures Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs. Results The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for theORF1abandE-genetargets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values. Conclusions and Relevance In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.

This study was aimed to investigate the expression characteristics of ETS variant 4 (ETV4) in gastric cancer (GCa), and to further explore whether it promotes the development of GCa by regulating KDM5D.Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to examine the expression of ETV4 in 35 pairs of tumor tissue and paracancerous tissue specimens collected from GCa patients, and the interplay between ETV4 expression and clinical indexes, as well as the prognosis of GCa patients, were analyzed. Meanwhile, the expression of ETV4 in GCa cell lines was verified using qRT-PCR assay. Furthermore, ETV4 knockdown model was constructed using lentivirus in GCa cell lines including AGS and BGC-823, and then, the transwell invasion and cell wound healing assays were applied to analyze the effect of ETV4 on the biological function of GCa cells. In addition, an in-depth study of the relationship between ETV4 and KDM5D was conducted.The results of qRT-PCR showed that the expression level of ETV4 in GCa tissue samples was remarkably higher than that in adjacent tissues, and the difference was statistically significant. Compared with patients with low expression of ETV4, the patients with high ETV4 expression had a higher occurrence rate of lymph node or distant metastasis and a lower overall survival rate. Similarly, the metastasis ability of GCa cells in the ETV4 expression knockdown group (sh-ETV4) was remarkably decreased when compared with the sh-NC group. In addition, qRT-PCR results indicated that the protein expression of KDM5D was significantly increased after the knockdown of ETV4. Therefore, it was demonstrated that ETV4 might be able to regulate the malignant progression of GCa via modulating KDM5D expression. Finally, the results of the cell reverse experiment confirmed that the silence of ETV4 could reverse the malignant progression of GCa induced by the downregulation of KDM5D.ETV4 expression was found remarkably elevated in GCa tissues and was significantly associated with the occurrence of lymph node or distant metastasis and poor prognosis. In addition, ETV4 might promote GCa cell metastasis by modulating KDM5D.

Wilms tumor demonstrates significant interethnic epidemiological, histological and outcome differences, and is rare and poorly studied among Asians. We compared the clinicopathological, and loss of heterozygosity (LOH) profile and survival outcomes of Asian and non-Asian patients with Wilms tumor. Clinical charts and histological slides from patients with malignant renal tumors over a period of 20 years were retrospectively reviewed. We adapted a genotyping assay to determine 1p36 and 16q21-22 LOH in formalin-fixed paraffin-embedded (FFPE) specimens, and compared these characteristics between Asian and non-Asian patients. Fifty-three (79.1%) Asian and 14 (20.9%) non-Asian patients had Wilms tumors. Compared to non-Asians, Asians were younger (mean 4.6 and 4.0 years, respectively), had more equal gender distribution (female: male = 1.8 and 1.0, respectively), fewer tumors with unfavorable histology (25.0% and 4.1%, respectively, p = 0.05), and less advanced disease at presentation, yet similar nodal metastases rates (16.7% and 18.4%, respectively). No Asian patients had bilateral tumors. Our adapted genotyping assay accurately determined LOH in FFPE specimens

Aims This study aims to examine the molecular genetics of paediatric breast fibroepithelial tumours through the targeted sequencing of 50 genes. Methods and results Formalin-fixed paraffin-embedded tissues of fibroepithelial tumours diagnosed in a cohort of patients aged 18 years and below were subjected to next generation sequencing using the Haloplex Target Enrichment System. Twenty-five conventional and 17 juvenile fibroadenomas were studied, with MED12 mutations found in 53.8 and 35% of the tumours, respectively. There was also one benign fibroepithelial neoplasm with hybrid features of juvenile papillomatosis and infarcted benign phyllodes tumour-like areas. Most tumours did not have mutations in well-known cancer driver genes, none harboured TERT promoter mutations, while 25.6% (11 of 43) showed no mutations. Metachronous and synchronous tumours were found to have mutational heterogeneity with some containing mutations in MED12; other genes or no mutations were detected at all. Four of eight giant fibroadenomas (size 5 cm or larger) had no mutations detected, suggesting that there are other molecular mechanisms driving their growth. Tumours with MED12 mutations incidentally had a significantly higher stromal mitotic count compared with those without. Conclusion While paediatric fibroepithelial lesions can have cellular stroma potentially raising concern for phyllodes tumour, their lack of TERT promoter and cancer driver mutations is reassuring. The absence of mutations in a significant proportion of tumours, especially the giant fibroadenomas, warrants investigation of pathogenetic mechanisms beyond those involving the 50 genes.

No large population-based study has focused on both maternal paternal risk factors for low birthweight (LBW) in China. We aimed to identify parental risk factors associated with LBW.A population-based, retrospective cohort study was conducted on 202,725 singleton infants at 37–42 weeks. These term singleton newborns were classified as LBW with birthweight ≤2500 g(TLBW) and normal birthweight between 50th to 97th percentile (TNBW 50th–97th) according to Chinese singleton norms. Multiple logistic regression analyses were used to find those parental risk factors of LBW by comparing two groups. TLBW and TNBW(50th–97th) occupied 4.8% and 70.8% of the study population, respectively. Logistic regression showed a significant association with positive maternal hepatitis B surface antigen (RR = 1.979, P = 0.047), irregular folic acid intake (RR = 1.152, P = 0.003), paternal history of varicocele (RR = 2.404, P = 0.003) and female babies (RR = 1.072, P = 0.046). Maternal smoking, hypertension and history of stillbirth were found related to LBW but no statistically significant. Positive maternal hepatitis B surface antigen, irregular folic acid intake, paternal history of varicocele had a negative effect on birth weight. Measures are necessarily taken to avoid them to improve pregnancy outcomes. Further studies should be done to investigate each detailed risk factors on LBW.

We describe the clinical, pathological, and molecular features of a primary adrenal angiomatoid fibrous histiocytoma (AFH) in an 11-year-old girl presenting with pyrexia of unknown origin. We performed next-generation sequencing-based anchored multiplex polymerase chain reaction (Archer® FusionPlex® sarcoma assay), which revealed an EWSR1-ATF1 gene fusion with novel breakpoints in exon 11 of EWSR1 and exon 3 of ATF1. The pyrexia resolved fully after surgical resection, and the patient was disease-free on follow-up at 1 year and 6 months. This case exemplifies the value of molecular testing of pediatric neoplasms presenting at unusual sites for diagnosis and identification of novel gene fusion breakpoints.

Clear cell sarcoma of the kidney (CCSK) is a rare paediatric renal malignant tumour. The majority of CCSKs have internal tandem duplications (ITDs) of the BCOR gene, whereas a minority have the YWHAE-NUTM2 gene fusion. A third 'double-negative' (DN) category comprises CCSKs with neither BCOR ITDs nor YWHAE-NUTM2 fusion. The aim of this study was to characterise 11 histologically diagnosed CCSKs immunohistochemically (with CCND1, BCOR and CCNB3 stains) and genetically.By next-generation sequencing, 10 cases (90.9%) had BCOR exon 15 ITDs, with positive BCOR immunoreactivity being found in four (36%) or eight (72%) cases, depending on the antibody clone. By reverse transcription polymerase chain reaction, none had the YWHAE-NUTM2 fusion. The DN case had a BCOR-CCNB3 fusion and strong nuclear CCNB3 and BCOR immunoreactivity. Quantitative polymerase chain reaction showed markedly elevated BCOR expression in this case, whereas BCOR ITD cases had lower levels of elevated BCOR expression.The majority of the CCSKs in our cohort had BCOR ITDs, and none had the YWHAE-NUTM2 fusion. We verified the strong, diffuse cyclin D1 (CCND1) immunoreactivity in CCSKs described in recent reports. BCOR immunoreactivity was not consistently positive in all CCSKs with BCOR ITDs, and therefore cannot be used as a diagnostic immunohistochemical stain to identify BCOR ITD cases. The DN case was a BCOR-CCNB3 fusion sarcoma. BCOR-CCNB3 sarcoma is typically a primary bone sarcoma affecting male adolescents, and this is the first report of it presenting in a kidney of a young child as a CCSK. The full spectrum of DN CCSKs awaits more comprehensive characterisation.

Lilium leichtlinii var. maximowiczii is known for its tolerance of cold and shade and its strong adaptability to the environment. To breed new cultivars with these traits, L. leichtlinii var. maximowiczii was used as male parent to hybridize with some Longiflorum × Asiatic (LA) cultivars, Asiatic cultivars and Lilium lancifolium. In 15 crossing combinations with LA cultivars, nine developed swollen ovaries and six showed high rates of seeds with embryos. In 11 crossing combinations with Asiatic cultivars, only three had embryo seeds. Four strains were randomly chosen from the seedlings of the crossing combination Lilium 'Renoir' (A) × L. leichtlinii var. maximowiczii, and were numbered B-1, B-2, B-3 and B-4. Fluorescence in situ hybridization (FISH) technology was used to detect the number and sites of 45S rDNA for the hybrid progeny and parents. The male parent had eight signals, all of which existed in pairs. Lilium 'Renoir' had seven 45S rDNA signals, some of which existed singly. B-1, B-2 and B-4 had eight 45S rDNA signals, while B-3 had nine. The four strains the signals on chromosome 6 as L. leichtlinii var. maximowiczii, near the end of the long arm. We conclude that they were true hybrids. Crossing combinations with natural triploid L. lancifolium also yielded high rates of seeds with embryos.

We report an experimental demonstration of a machine learning approach to identify exotic topological phases, with a focus on the three-dimensional chiral topological insulators. We show that the convolutional neural networks---a class of deep feed-forward artificial neural networks with widespread applications in machine learning---can be trained to successfully identify different topological phases protected by chiral symmetry from experimental raw data generated with a solid-state quantum simulator. Our results explicitly showcase the exceptional power of machine learning in the experimental detection of topological phases, which paves a way to study rich topological phenomena with the machine learning toolbox., Main text: 5 pages with 3 figures; supplemental materials: 8 pages with 4 figures and 2 tables; accepted at Physical Review Letters

In components built by selective laser melting (SLM), possible anisotropy in microstructure significantly affects mechanical properties (i.e. service performance) and there is a constant effort to solve this problem. This work carried out a comparative study using fully dense AlSi10Mg alloy and in-situ nano-TiB2 decorated AlSi10Mg composite samples processed by SLM. The aim was at clarifying the effect of integrated nanoparticles on the anisotropy of the as-built component. Microstructure and texture evolution were investigated by scanning and transmission electron microscopy, electron backscatter diffraction, X-ray and neutron diffraction. The SLMed AlSi10Mg sample shows a coarse columnar grain structure with and fiber orientation texture and obvious anisotropy in mechanical properties. However, the nano-TiB2 modified AlSi10Mg sample exhibits fine equiaxed grains, no preferred crystallographic texture and remarkably reduced anisotropy. Besides, both tensile strength and ductility have been improved in the SLMed TiB2 decorated AlSi10Mg sample. The preliminary mechanism upon grain refinement effect due to nano-TiB2 particles on columnar-to-equiaxed transition and reduction of anisotropy was discussed.

We experimentally realize a universal set of single-bit and two-bit geometric quantum gates by adiabatically controlling solid-state spins in a diamond defect. Compared with the nonadiabatic approach, the adiabatic scheme for geometric quantum computation offers a unique advantage of inherent robustness to parameter variations, which is explicitly demonstrated in our experiment by showing that the single-bit gates remain unchanged when the driving field amplitude varies by a factor of 2 or the detuning fluctuates in a range comparable to the inverse of the gate time. The reported adiabatic control technique and its convenient implementation offer a paradigm for achieving quantum computation through robust geometric quantum gates, which is important for quantum information systems with parameter-fluctuation noise such as those from the inhomogeneous coupling or the spectral diffusion.

Selective laser melting (SLM) of aluminium alloys is of research interest due to its potential benefits in fabricating complex components for aerospace and automotive industries. In order to improve the mechanical properties and demonstrate the credibility of selective laser melted (SLMed) Al alloys, the effects of post heat treatment on the microstructures and mechanical properties need to be studies. In the present work, the nano-TiB2 decorated Al–7Si–Cu–Mg samples were successfully fabricated using the SLM technique, and then post-treated by direct ageing and conventional T6 heat treatment. The as-built TiB2/Al–7Si–Cu–Mg sample exhibits fine equiaxed grain structures without preferred crystallographic texture due to the high cooling rate of SLM and the addition of nano-TiB2 particles. Nano-scale eutectic Si cells are present within the equiaxed grains. Inside the cells, there are dislocation tangles without precipitates. After direct ageing treatment, the grain and cell structures remain almost unchanged, and the new Al2Cu, Mg2Si, and Si phases are formed around the dislocations. While after T6 treatment, the fine grains grow up and the eutectic Si phases coarse leading to the broken of cell structures. Besides, the as-built TiB2/Al–7Si–Cu–Mg samples show high tensile strength and ductility (yield strength: 297.2 MPa, ultimate tensile strength: 474.6 MPa, elongation: 13.4%). During ageing, the yield strength is enhanced by ~35% due to precipitation hardening effect. While the broken of fine microstructure during T6 leads to the decrease of yield strength by ~16%. The microstructure development and preliminary strengthening mechanism were discussed. The effect of post-heat treatments can yield the SLMed TiB2/Al–7Si–Cu–Mg samples with appropriate mechanical properties, promoting a wide range of applications.

In fires, reinforced concrete (RC) columns in the subway stations were seriously threatened by high-temperature gas fumes. In this paper, an axial compressive simulation test that involved eight RC columns was undertaken to investigate the effect of high-temperature gas fume on RC columns. Two of them were control specimens with different cross sections. The others were exposed to high-temperature gas fumes. The specimens were heated to 300, 400, and 500 °C. The effects of high-temperature degree on ultimate load capacity and failure mode were investigated. As the applied load was increased, the crack gradually spread to the unheated area. Meanwhile, the initial stiffness and energy dissipation capacity were also summarized. The test results show that the ultimate load capacity and initial stiffness of RC columns decreased sharply with the increase in temperature. Compared to unexposed RC columns with circle cross section, the ultimate load capacity of specimens exposed to high temperature decreased by 47.9, 56.0 and 67.9%. The initial stiffness of RC columns with circle cross section exposed to 500 °C was 13 times lower than those of unexposed RC columns. The energy ductility of RC columns increased with the flue gas temperature. Furthermore, an analytical model was established to predict the residual axial load-carrying capacity of RC columns. It was demonstrated that the analytical model is correct and the predicted results are consistent with experimental results.

Aim The role of ischemia in the pathogenesis of necrotizing enterocolitis (NEC) remains unclear. We used immunohistochemical markers of hypoxia to identify presence/absence of ischemia in NEC and spontaneous intestinal perforation (SIP) with clinical correlation. Methods Immunohistochemical staining was performed on 24 NEC and 13 SIP intestinal resection specimens using 2 hypoxia markers, hypoxia inducible factor 1α (HIF-1α) and glucose transporter 1 (GLUT1) and inflammatory markers, leukocyte common antigen (LCA) and myeloperoxidase. Ischemic score (0-6) from the sum of the HIF-1α and GLUT1 staining intensity grades was devised (positive ≥3). Inflammation was graded from the sum of LCA and myeloperoxidase grading. Relevant clinical information was obtained from hospital case records. Results Fourteen NEC specimens had positive ischemic score (4.6±1.2). The remaining 10 NEC (ischemic score 0.7±0.8) and all 13 SIP samples (ischemic score 0.5±0.5) were ischemic-negative. The ischemic-positive cases had classic NEC with multiple areas of bowel necrosis; were associated with later onset, enteral feeding and pneumatosis. In contrast, all ischemic-negative NEC were short-segment NEC with perforation. Their clinical profile was similar to the SIP cases with younger gestational age at birth, early onset, association with ibuprofen/indomethacin usage but not with feeding and pneumatosis. Ischemic scores are correlated with inflammation scores in mucosa but not submucosa. Conclusions Ischemia as assessed with immunohistochemical markers HIF-1α and GLUT1, has a primary role in pathogenesis of classic NEC only, not in SIP or short-segment NEC with perforation. Better categorization of the different types of NEC can direct appropriate prevention and treatment strategies.

T cell dysfunction has a crucial role in establishing and maintaining viral persistence. We have previously shown a decline in miR-181a, which regulates CD4+ T cell responses via DUSP6 overexpression, in individuals with hepatitis C virus (HCV) infection. Here, we describe accelerated T cell senescence in HCV-infected individuals compared with age- and sex-matched healthy subjects. Mechanistic studies revealed that up-regulation of transcription factor ΔNp63 led to the decline of miR-181a expression, resulting in an overexpression of the antiaging protein Sirt1, in CD4+ T cells from HCV-infected individuals. Either reconstituting miR-181a or silencing ΔNp63 or Sirt1 expression in CD4+ T cells led to accelerated T cell senescence, as evidenced by an increased senescence-associated β-galactosidase (SA-β-gal) expression, shortened telomere length, and decreased EdU incorporation; this suggests that HCV-induced T cell senescence is counterregulated by the ΔNp63–miR-181a–Sirt1 pathway. An increase of IL-2 production was observed in these senescent CD4+ T cells and was driven by a markedly reduced frequency of Foxp3+ regulatory T (Treg) cells and increased number of Foxp3− effector T (Teff) cells upon manipulating the ΔNp63–miR-181a–Sirt1 pathway. In conclusion, these findings provide novel mechanistic insights into how HCV uses cellular senescent pathways to regulate T cell functions, revealing new targets for rejuvenating impaired T cell responses during chronic viral infection.

Langerhans Cell Histiocytosis is a rare disease featuring aberrant proliferation of dendritic cells that can infiltrate the bony skeleton. The authors report a case of six-year-old female presenting with torticollis. She was found to have extensive lytic LCH lesions in the cranio-cervical junction, causing atlanto-axial rotatory subluxation. Decision was made for a non-surgical approach to treat the patient. She was placed in a Halo brace, and given concomitant chemotherapy. Post-treatment imaging demonstrated near-complete reconstitution of the skeleton affected by LCH. This case highlights the feasibility of non-surgical treatment in selected LCH patients at high-risk of spinal instability. Keywords: Atlanto-axial subluxation, Langerhans cell histocytosis, Torticollis

This study is aimed to synthesize ZrB2–SiC composite powders by boro-carbothermal reduction of zircon using two different carbon sources, namely expanded graphite and carbon black. The effect of carbon sources on the phase composition and microstructure of composite powders was studied using an X-ray diffractometer, a scanning electron microscope, and an energy spectrum analyzer. Pure-phase ZrB2–SiC composite powders were prepared in 2 h at 1550 and 1500 °C 1500 °C using expanded graphite and carbon black, respectively. In the former case, anisotropic ZrB2–SiC composite powders were synthesized. Their ZrB2phase grains had an average diameter of 2.0 μm and regular hexagonal shape, while SiC phase grains were whisker-shaped, had an average diameter of 0.15 μm and aspect ratio exceeding 20. For carbon black, finer ZrB2grains and shorter rod-shaped SiC grains were obtained.

Introduction: Massive perivillous fibrinoid deposition (MPFD) is a very rare placental condition characterized by abnormally extensive fibrinoid deposition in the placental villous parenchyma. The aim of this study is to document clinical and pathological features with special focus on pregnancy outcomes of this condition in consecutive cases of MPFD in our local population. Methods: This is a retrospective clinico-pathological study of cases affected by MPFD over the period January 2010–July 2014 in our hospital. We document clinical features (including perinatal outcome and subsequent pregnancies) and placental pathological characteristics. Results: Twelve cases of MPFD were identified among 3640 placentas (0.33%). There was no identified recurrence. The affected infants had adverse outcomes, including intrauterine growth restriction (IUGR) (75%), preterm birth (58.3%), and fetal loss (25%). A high frequency of reduced PAPP-A in the first trimester (25%), and concurrent gestational hypertension or pre-eclampsia (25%) was noted. Conclusion: MPFD is associated with adverse perinatal outcomes. Further research to better understand its pathogenesis and to improve clinical diagnosis and management is warranted.

Pathological diagnosis of clear cell sarcoma of the kidney (CCSK) is challenging as it resembles blastemal Wilms tumor (WT) and other pediatric sarcomas, and does not have any distinctive immunophenotype. The YWHAE-FAM22 translocation t(10;17)(q22;p13) has been reported in a subset of CCSK. This translocation also occurs in high-grade endometrial sarcoma, in which it is associated with cyclin D1 overexpression. Hence we seek to determine YWHAE-FAM22 translocation status and cyclin D1 immunoreactivity in a series of local CCSK cases. Of 8 CCSK cases from 7 patients identified, no CCSK had the YWHAE-FAM22 fusion transcript by reverse transcriptase–polymerase chain reaction. Novel karyotypes were identified for 2 cases: 1 had t(2;13)(q13; q22) and the other t(3:17)(q29;p11.2). Excluding a case with poor tissue section antigenicity, 7 of 7 CCSKs (100%) showed diffuse and strong nuclear cyclin D1 staining. Cyclin D1 immunohistochemistry was also performed on tissue microarrays of other pediatric renal tumors: blastemal areas of 18 WT cases were negative; 6 rhabdoid tumors and 1 metanephric adenoma showed patchy and weak staining; 3 mesoblastic nephromas and 18 of 29 neuroblastomas had positive staining. Cyclin D1 immunohistochemistry helps distinguish CCSK from blastemal WT and metanephric adenoma and rhabdoid tumors, but not from neuroblastomas and mesoblastic nephromas. Cyclin D1 overexpression in CCSK is not contingent on YWHAE-FAM22 translocation, and cyclin D1 inhibition may potentially be explored as a targeted therapeutic strategy in CCSK.

Xeroderma pigmentosum (XP) is an autosomal recessive genodermatosis caused by a germline loss of function in DNA repair enzymes.1, 2 This defect impairs physiologic DNA repair after ultraviolet (UV) radiation–induced damage, which can lead to photosensitivity in about half of all patients,3, 4 pigmentation abnormalities, and an increased risk of nonmelanoma skin cancers as well as melanoma.5 XP patients classically exhibit a 10,000-fold increase in the frequency of skin cancers arising in sun-exposed skin, eyes, and other mucosal areas (eg, lips and tongue), which appear at an early age.5 Prognosis and mortality of XP patients are mostly tightly related to the risk of metastasis of cutaneous squamous cell carcinomas and melanomas but also depend on the extent of the underlying DNA repair deficiency. The life expectancy of XP patients is reduced by 30 years.2, 6 Seven genetically distinct complementation groups of XP (designated XP-A through XP-G depending on the gene mutated) with germline loss of function mutations to enzymes are involved in nucleotide excision repair (NER).6 The degree of photosensitivity, risk of skin cancer, and risk of neurologic abnormality vary from complementation group to group.3 XP complementation group G (XP-G, OMIM 278780) represents one of the rarest subtypes of XP with mutations identified in the Excision Repair Cross-complementing Rodent Repair Deficiency Complementation Group 5 gene (ERCC5), which encodes an enzyme involved in the incision step during the removal of UV-damaged DNA. XP-G is one of the most clinically lethal subtypes of XP, wherein patients also exhibit clinical features of Cockayne syndrome (CS) or XP with neurologic symptoms. To date, there have been less than 20 XP-G cases reported in the literature.7, 8 Approximately 30 noncutaneous malignancies have also been associated with this lethal XP subtype.9 Herein, we report a Chinese proband patient who had XP group G diagnosed, resulting from 2 compound heterozygous germline mutations in ERCC5—a nonsense mutation from the father and a missense mutation from the mother. To the best of our knowledge, this patient is the first reported XP-G case identified in the Chinese population.

BackgroundBirth weight is a critical indicator of neonatal health and foretells people’s health in adolescence and even adulthood. Some researchers have warned against the adverse effects on babies’ birth weight of exposure to pollutants in interior decoration or oil paint by odour intake. This study evaluated the effects of maternal exposure to such factors before conception on the birth weights of neonates.MethodsData on 213 461 cases in this study were from the database of the free National Pre-pregnancy Checkups Project. Defined as ‘exposed’ were those women exposed to oil paint odour or interior decoration at home or in the workplace within 6 months before their pregnancy. The study focused on revealing the correlation between such exposure and the birth weight of the neonates of these women, especially the incidence of macrosomia and low birth weight (LBW). Statistical analysis was conducted using the Kruskal–Wallis H test, the Mann–Whitney U test and logistic regression.ResultsThe birth weight of babies from mothers non-occupationally exposed to such settings averaged 3465 g (range 3150–3650 g), whereas the birth weight of those from mothers free of such exposure averaged 3300 g (range 3000–3600g). Maternal exposure preconception to interior decoration or oil paint odour reduced the incidence of LBW in their babies (p=0.003, OR 0.749, 95% CI 0.617 to 0.909). Such exposure may also augment the probability of macrosomia (pConclusionMaternal exposure to interior decoration or oil paint odour preconception may increase the average birth weight of neonates, as well as the incidence of macrosomia.

Background Preterm birth and small for gestational age (SGA) are strong indicators of neonatal adverse outcomes. With the growing importance of preterm SGA infants, we aim to evaluate the prevalence and risk factors for preterm SGA in China. Method We analyzed the data of parents and infants from a population-based cohort research of the free National Pre-pregnancy Checkups Project (NPCP) in rural China. Only singleton live births that occurred between 24 weeks +0 days and 36 weeks +6 days of pregnancy were included in this study. SGA was defined as birth weight less than the 10th percentile of the reference birth-weight-for-gestational-age population. A multiple logistic regression model was built using the statistically significant variables from the 371 variables in the questionnaire. Results A total of 11,474 singleton, preterm, live-birth infants were included. Of the total infants, 317 (2.77%) were preterm SGA infants. A higher risk of preterm SGA infants was observed among mothers who were on oral contraceptives (OR: 8.162, 95% CI: 1.622–41.072), mothers who had syphilis (OR: 12.800, 95% CI: 1.250–131.041), and mothers with a high eosinophil percentage (OR: 13.292, 95% CI: 1.282–135.796). Maternal intake of folic acid at least 3 months before pregnancy (OR: 0.284, 95% CI:0.124–0.654) and paternal intake of egg and meat (OR: 0.097,95% CI:0.030–0.315) were protective factors. Compared with North China, the incidence of preterm SGA infants was higher in South China. Conclusion Preterm SGA infants were associated with both maternal and paternal factors.

A 3-year-old boy presented with pathologic fracture of the left proximal femur. Magnetic resonance imaging revealed an aggressive expansile bony mass associated with cortical destruction and surrounding myositis. Computed tomography-guided biopsy revealed a monomorphic small round blue cell tumor by histology. CD99 immunoreactivity and low-level EWSR1 gene translocation by break-apart fluorescent in situ hybridization initially favored a diagnosis of Ewing sarcoma and chemotherapy commenced. Subsequent molecular evaluation by an anchored multiplex polymerase chain reaction-based assay (Archer FusionPlex Sarcoma Panel) revealed a nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) gene fusion. The diagnosis was then amended to primary bone ALK-positive anaplastic large cell lymphoma and the chemotherapy regimen was modified accordingly. This report illustrates the value of this molecular assay in establishing the correct diagnosis of a very rare malignancy masquerading as another tumor type.