Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.

Ancient Egyptian mummy genomes suggest an increase of Sub-Saharan African ancestry in post-Roman periods.

Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level.

Short-term intravenous fish-oil emulsions in pediatric oncologic patients--effect on liver parameters.

Pediatric oncologic patients often need parenteral nutrition (PN) during chemotherapy. Long-term use of soybean-based lipid emulsions is associated with progressive liver disease and cholestasis, whereas fish-oil based emulsions have anticholestatic effects. We studied the potentially hepato-protective effects of short-term use of SMOF lipids in children undergoing chemotherapy. Fifteen pediatric oncologic patients treated with SMOF lipids were retrospectively analyzed in respect to bilirubin and liver parameters and compared to matched-controls who had received soybean-based fat emulsions. For statistics the time-points baseline, Day 14 of PN (PN14), and post (Day+7) were chosen. None of the study patients developed cholestasis. Within the SMOF-lipid group there were no differences in the laboratory parameters between baseline, PN14, and post. In the control group, gamma glutamyltransferase (γGT) levels increased during PN (baseline vs. PN14, 26.43 vs. 63.00 U/l, P < 0.05). Lactate dehydrogenase (LDH) levels showed a significantly different behavior in the 2 groups: In the SMOF lipids group, LDH decreased whereas it increased in the controls (-32.75 U/l vs. + 29.57 U/l, P < 0.05). An advantage of fish oil-based fat emulsions can be shown even after short-term PN. In children undergoing chemotherapy the use of soybean-based fat emulsions but not SMOF lipids led to increased γGT levels.

Retinoblastoma: a proposal for a multimodal treatment concept for intraocular retinoblastoma in Austria.

Retinoblastoma is the most common intraocular malignancy in childhood. If confined to the globe and managed with current treatment strategies, more than 90% of children survive with preservation of vision in at least one eye, even in bilateral retinoblastoma. Enucleation of the involved eye in unilateral retinoblastoma and of the more involved eye in bilateral disease, together with external beam radiotherapy in advanced bilateral retinoblastoma, formed the two cornerstones of treatment for many years and led to an increase in survival to over 90%. In the early 1990s the extent of the risk of second cancers in the field of radiation became known, the risk increasing by 10% per decade of life. As a consequence, chemotherapy-based regimens were developed as alternative treatments. During the past ten years retinoblastoma treatment has fundamentally changed, with a trend away from enucleation and external beam radiotherapy towards conservative treatments aiming at preservation of the affected globe(s) in selected patients. Systemic neoadjuvant chemotherapy induces tumor regression (chemoreduction), and residual regressed tumor is then treated focally with, for example, transpupillary thermotherapy, cryotherapy and plaque radiotherapy (consolidation). Between 1984 and 2004, 27 patients were treated at the department of ophthalmology in collaboration with the department of pediatrics at the Medical University of Graz. Before 2001, the affected eyes of all patients with unilateral retinoblastoma were enucleated (10 of 10), as were 6 of 7 of the more involved eyes of patients with bilateral disease. A globe-sparing strategy was introduced in 2001 and since then eligible patients have been treated with chemoreduction and focal therapy; 2 of 5 eyes with unilateral disease were salvaged, and both eyes of a patient with bilateral disease. We discuss current treatment options and present a proposal for the management of intraocular retinoblastoma in children in Austria, the Austrian retinoblastoma study, RB A-2003.

Multimodal treatment of children with unresectable or recurrent desmoid tumors: an 11-year longitudinal observational study.

The primary goal of treatment for desmoid tumors is complete surgical resection to achieve negative margins. In adults with unresectable or recurrent lesions, treatment options include noncytotoxic and cytotoxic drugs, but little is known about nonsurgical treatment in children. Between 1992 and 2003 six children (four girls, two boys) with a median age of 2.5 years (range 11 months to 9 years) received multimodal adjuvant therapy for unresectable or recurrent desmoid tumors. Primary treatment consisted of noncytotoxic treatment with tamoxifen (1 mg/kg orally, twice daily) and diclofenac (2 mg/kg rectally, twice daily), whereas two children with life-threatening tumor progression in addition received treatment intensification with weekly vinblastine (6 mg/m intravenously) and methotrexate (30 mg/m intravenously). Of the four children with unresectable tumors, two achieved remarkable tumor shrinkage and two had stable disease, whereas two patients were disease-free for 3.7 and 2.6 years after nonradical resection. Median observation time was 3.1 years (range 1-11 years). Treatment was generally well tolerated; only one patient developed pubertal acceleration after a duration of tamoxifen treatment of 9.3 years. Because of the potential life-threatening situation, the management of children with unresectable or recurrent desmoid tumors requires a multidisciplinary approach. Nonaggressive therapy with tamoxifen and diclofenac may be the first treatment choice in these patients, but in patients with progressive disease, cytotoxic chemotherapy is indicated. Weekly administration of vinblastine and methotrexate seems to be safe and effective in these children.