Late solitary bone metastasis of a primary pulmonary synovial sarcoma with SYT-SSX1 translocation type: case report with a long follow-up

Primary synovial sarcoma outside its classical presentation in para-articular soft tissue of young patients is rare but regularly reported. One of the rarest primary locations is the lung. We describe a 73-year-old female patient who presented with a solitary malignant bone tumor 8years after the resection of a lung neoplasm. The bone tumor was classified as an osteosarcoma and the lung tumor as an atypical carcinoid tumor at their first respective diagnostic work-ups. The resection of the affected humerus with allograft and endoprosthesis implantation followed. Reevaluation of the tumor samples at the time of the local recurrence of the bone tumor 6years following the initial symptoms of the bone tumor lead to the reclassification of both specimens as synovial sarcomas. Both neoplasms contained the SYT-SSX1 type of the diagnostic translocation t(X;18) as detected by the reverse-transcription polymerase chain reaction analysis. The patient died 14years after the resection of the primary synovial sarcoma of the lung and 6years following the occurrence of the bone metastasis. This prolonged clinical course is uncommon for the SYT-SSX1 translocation, which, in other locations, is usually associated with an unfavorable prognosi

Digital multiplex ligation assay for highly multiplexed screening of beta-lactamase-encoding genes in bacterial isolates

Increasing incidence of antibiotic resistance in clinical and environmental settings calls for increased scalability in their surveillance. Current screening technologies are limited by the number of samples and genes that can easily be screened. We demonstrate here digital multiplex ligation assay (dMLA) as a low-cost targeted genomic detection workflow capable of highly-parallel screening of bacterial isolates for multiple target gene regions simultaneously. Here, dMLA is used for simultaneous detection of 1187 beta-lactamase-encoding genes, including extended spectrum beta-lactamase (ESBL) genes, in 74 bacterial isolates. We demonstrate dMLA as a light-weight and cost-efficient workflow which provides a highly scalable tool for antimicrobial resistance surveillance and is also adaptable to genetic screening applications beyond antibiotic resistance.Tamminen et al. develop a digital multiplex ligation assay (dMLA) that enables the detection of bacterial isolates using probe hybridization and ligation-based assays with next-generation sequencing. Their method can be applied in high-throughput and affordable screening for antibiotic resistance

Early detection and surveillance of SARS-CoV-2 genomic variants in wastewater using COJAC

The continuing emergence of SARS-CoV-2 variants of concern and variants of interest emphasizes the need for early detection and epidemiological surveillance of novel variants. We used genomic sequencing of 122 wastewater samples from three locations in Switzerland to monitor the local spread of B.1.1.7 (Alpha), B.1.351 (Beta) and P.1 (Gamma) variants of SARS-CoV-2 at a population level. We devised a bioinformatics method named COJAC (Co-Occurrence adJusted Analysis and Calling) that uses read pairs carrying multiple variant-specific signature mutations as a robust indicator of low-frequency variants. Application of COJAC revealed that a local outbreak of the Alpha variant in two Swiss cities was observable in wastewater up to 13 d before being first reported in clinical samples. We further confirmed the ability of COJAC to detect emerging variants early for the Delta variant by analysing an additional 1,339 wastewater samples. While sequencing data of single wastewater samples provide limited precision for the quantification of relative prevalence of a variant, we show that replicate and close-meshed longitudinal sequencing allow for robust estimation not only of the local prevalence but also of the transmission fitness advantage of any variant. We conclude that genomic sequencing and our computational analysis can provide population-level estimates of prevalence and fitness of emerging variants from wastewater samples earlier and on the basis of substantially fewer samples than from clinical samples. Our framework is being routinely used in large national projects in Switzerland and the UK

Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus

BACKGROUND: Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown. METHODS AND FINDINGS: We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained. Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean ± standard error of the mean: 7.5 ± 1.6 min). CONCLUSIONS: A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia

Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels

Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density

Genomic aberrations in borderline ovarian tumors

<p>Abstract</p> <p>Background</p> <p>According to the scientific literature, less than 30 borderline ovarian tumors have been karyotyped and less than 100 analyzed for genomic imbalances by CGH.</p> <p>Methods</p> <p>We report a series of borderline ovarian tumors (n = 23) analyzed by G-banding and karyotyping as well as high resolution CGH; in addition, the tumors were analyzed for microsatellite stability status and by FISH for possible 6q deletion.</p> <p>Results</p> <p>All informative tumors were microsatellite stable and none had a deletion in 6q27. All cases with an abnormal karyotype had simple chromosomal aberrations with +7 and +12 as the most common. In three tumors with single structural rearrangements, a common breakpoint in 3q13 was detected. The major copy number changes detected in the borderline tumors were gains from chromosome arms 2q, 6q, 8q, 9p, and 13q and losses from 1p, 12q, 14q, 15q, 16p, 17p, 17q, 19p, 19q, and 22q. The series included five pairs of bilateral tumors and, in two of these pairs, informative data were obtained as to their clonal relationship. In both pairs, similarities were found between the tumors from the right and left side, strongly indicating that bilaterality had occurred via a metastatic process. The bilateral tumors as a group showed more aberrations than did the unilateral ones, consistent with the view that bilaterality is a sign of more advanced disease.</p> <p>Conclusion</p> <p>Because some of the imbalances found in borderline ovarian tumors seem to be similar to imbalances already known from the more extensively studied overt ovarian carcinomas, we speculate that the subset of borderline tumors with detectable imbalances or karyotypic aberrations may contain a smaller subset of tumors with a tendency to develop a more malignant phenotype. The group of borderline tumors with no imbalances would, in this line of thinking, have less or no propensity for clonal evolution and development to full-blown carcinomas.</p

Loss of Secreted Frizzled-Related Protein 4 Correlates with an Aggressive Phenotype and Predicts Poor Outcome in Ovarian Cancer Patients

Background: Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. Methodology/Principal Findings: We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Conclusions/Significance: Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets

Tumour vascularization: sprouting angiogenesis and beyond

Tumour angiogenesis is a fast growing domain in tumour biology. Many growth factors and mechanisms have been unravelled. For almost 30 years, the sprouting of new vessels out of existing ones was considered as an exclusive way of tumour vascularisation. However, over the last years several additional mechanisms have been identified. With the discovery of the contribution of intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option, vasculogenic mimicry and lymphangiogenesis to tumour growth, anti-tumour targeting strategies will be more complex than initially thought. This review highlights these processes and intervention as a potential application in cancer therapy. It is concluded that future anti-vascular therapies might be most beneficial when based on multimodal anti-angiogenic, anti-vasculogenic mimicry and anti-lymphangiogenic strategies

Ebola: translational science considerations

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as “Ebola”, ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective