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Many therapeutic agents target the ERBB family of receptor tyrosine kinases in various cancers. This Opinion article describes our latest understanding of the value of combining inhibitors directed towards an individual ERBB family member, including the molecular mechanisms of synergy and progress in clinical trials. The ERBB family of receptor tyrosine kinases has a central role in the tumorigenesis of many types of solid tumour. Various therapeutics targeting these receptors have been approved for the treatment of several cancers. Considerable preclinical data have shown that the administration of two inhibitors against an individual ERBB family member — particularly epidermal growth factor receptor (EGFR) or ERBB2 — leads to markedly higher antitumour activity than the administration of single agents. This Opinion article describes the preclinical and clinical performance of these dual-targeting approaches, discusses the key mechanisms that mediate their increased efficacy and highlights areas for ongoing investigation.

During the Last Glacial Maximum, continental ice sheets isolated Beringia (northeast Siberia and northwest North America) from unglaciated North America. By around 15 to 14 thousand calibrated radiocarbon years before present (cal. kyr bp ), glacial retreat opened an approximately 1,500-km-long corridor between the ice sheets. It remains unclear when plants and animals colonized this corridor and it became biologically viable for human migration. We obtained radiocarbon dates, pollen, macrofossils and metagenomic DNA from lake sediment cores in a bottleneck portion of the corridor. We find evidence of steppe vegetation, bison and mammoth by approximately 12.6 cal. kyr bp , followed by open forest, with evidence of moose and elk at about 11.5 cal. kyr bp , and boreal forest approximately 10 cal. kyr bp . Our findings reveal that the first Americans, whether Clovis or earlier groups in unglaciated North America before 12.6 cal. kyr bp , are unlikely to have travelled by this route into the Americas. However, later groups may have used this north–south passageway. During much of the last ice age, continental ice sheets prevented humans from migrating into North America from Siberia; an environmental reconstruction of the corridor that opened up between the Cordilleran and Laurentide ice sheets reveals that it would have been inhospitable to the initial colonizing humans, who therefore probably entered North America by a different route. A coastal migration route to the Americas During much of the last ice age, continental ice sheets prevented humans from migrating into North America from Beringia, the area between Siberia and what is now the Bering Strait. At some point, a route opened up between the Cordilleran and Laurentide ice sheets, but it is thought that this 1,500-kilometre-long ice-free corridor may have been too cold to act as a human migration route. Eske Willerslev and colleagues present a series of environmental reconstructions based on coring of lake sediments in what was once the ice-free corridor. Their data indicate that the corridor would have still been inhospitable even after humans are known to have arrived in the Americas south of the ice. This implies that humans migrated by a coastal route, now submerged by the risen sea.

Antibody combinations targeting cell surface receptors are a new modality of cancer therapy. The trafficking and signalling mechanisms regulated by such therapeutics are not fully understood but could underlie differential tumour responses. We explored EGFR trafficking upon treatment with the antibody combination Sym004 which has shown promise clinically. Sym004 promoted EGFR endocytosis distinctly from EGF: it was asynchronous, not accompanied by canonical signalling events and involved EGFR clustering within detergent-insoluble plasma mebrane-associated tubules. Sym004 induced lysosomal degradation independently of EGFR ubiquitylation but dependent upon Hrs/Tsg101 that are required for the formation of intraluminal vesicles (ILVs) within late endosomes. We propose Sym004 cross-links EGFR physically triggering EGFR endocytosis and incorporation onto ILVs and so Sym004 sensitivity correlates with EGFR numbers available for binding, rather than specific signalling events. Consistently Sym004 efficacy and potentiation of cisplatin responses correlated with EGFR surface expression in head and neck cancer cells. These findings will have implications in understanding the mode of action of this new class of cancer therapeutics.

Abstract Over the past few decades, there has been a growing demand for genome analysis of ancient human remains. Destructive sampling is increasingly difficult to obtain for ethical reasons, and standard methods of breaking the skull to access the petrous bone or sampling remaining teeth are often forbidden for curatorial reasons. However, most ancient humans carried head lice and their eggs abound in historical hair specimens. Here we show that host DNA is protected by the cement that glues head lice nits to the hair of ancient Argentinian mummies, 1,500–2,000 years old. The genetic affinities deciphered from genome-wide analyses of this DNA inform that this population migrated from north-west Amazonia to the Andes of central-west Argentina; a result confirmed using the mitochondria of the host lice. The cement preserves ancient environmental DNA of the skin, including the earliest recorded case of Merkel cell polyomavirus. We found that the percentage of human DNA obtained from nit cement equals human DNA obtained from the tooth, yield 2-fold compared with a petrous bone, and 4-fold to a bloodmeal of adult lice a millennium younger. In metric studies of sheaths, the length of the cement negatively correlates with the age of the specimens, whereas hair linear distance between nit and scalp informs about the environmental conditions at the time before death. Ectoparasitic lice sheaths can offer an alternative, nondestructive source of high-quality ancient DNA from a variety of host taxa where bones and teeth are not available and reveal complementary details of their history.

Traditional zooarchaeological and archaeobotanical methods based on morphological identification of the excavated faunal and floral remains have been broadly used in reconstructing ancient subsistence economies. However, the accuracy and reliability of these methods rely heavily on the preservation state of the remains. By sequencing the ancient DNA of plants, animals, and microorganisms preserved in sediment, sedimentary ancient DNA (sedaDNA) now offers a novel approach for reconstructing the taxa composition dated back to hundreds of thousands of years. Yet, its application in open-air archaeological sites is rarely reported. In this study, we attempted to apply sedaDNA shotgun metagenomics on the archaeological deposits of the Khog Gzung site (an open-air site dated to 3160–2954 cal yr BP) on the Tibetan Plateau, and then compared the reconstructed taxonomic composition to the unearthed remains. Results showed that most of the crops and domestic animals identified by the two approaches, such as barley ( Hordeum vulgare ) and sheep ( Ovis aries ), are in general consistent. Some species, such as foxtail millet ( Setaria italica ), however, was only detected by sedaDNA. In addition, a variety of microorganisms were also detected by the sedaDNA. The two approaches combined revealed diversified food recourses at the Khog Gzung site, which included crops such as millet, barley and wheat, domestic animals such as sheep and cattle, and likely also wild animals from fishing and hunting. Our data proves that sedaDNA has a great potential in reconstructing the faunal and floral compositions from archaeological deposits, therefore laying the foundation for its border applications.

The human epidermal growth factor receptor 2 (HER2/ErbB2) is overexpressed in a number of human cancers. HER2 is the preferred heterodimerization partner for other epidermal growth factor receptor (EGFR) family members and is considered to be resistant to endocytic down‐regulation, properties which both contribute to the high oncogenic potential of HER2. Antibodies targeting members of the EGFR family are powerful tools in cancer treatment and can function by blocking ligand binding, preventing receptor dimerization, inhibiting receptor activation and/or inducing receptor internalization and degradation. With respect to antibody‐induced endocytosis of HER2, various results are reported, and the effect seems to depend on the HER2 expression level and whether antibodies are given as individual antibodies or as mixtures of two or more. In this study, the effect of a mixture of two monoclonal antibodies against non‐overlapping epitopes of HER2 was investigated with respect to localization and stability of HER2. Individual antibodies had limited effect, but the combination of antibodies induced internalization and degradation of HER2 by multiple endocytic pathways. In addition, HER2 was phosphorylated and ubiquitinated upon incubation with the antibody combination, and the HER2 kinase activity was found to be instrumental in antibody‐induced HER2 down‐regulation.

SummaryPurpose. Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced epithelial malignancies. Methods. Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies. Results. Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease. Conclusion. During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely.Trial registry: www.clinicaltrials.gov; NCT02906670 (September 20, 2016).

BackgroundSym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII).MethodsTo address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models.ResultsIn vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture.ConclusionThese results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.

The human epidermal growth factor receptor 2 ( HER 2/ErbB2) is overexpressed in a number of human cancers. HER 2 is the preferred heterodimerization partner for other epidermal growth factor receptor ( EGFR ) family members and is considered to be resistant to endocytic down‐regulation, properties which both contribute to the high oncogenic potential of HER 2. Antibodies targeting members of the EGFR family are powerful tools in cancer treatment and can function by blocking ligand binding, preventing receptor dimerization, inhibiting receptor activation and/or inducing receptor internalization and degradation. With respect to antibody‐induced endocytosis of HER 2, various results are reported, and the effect seems to depend on the HER 2 expression level and whether antibodies are given as individual antibodies or as mixtures of two or more. In this study, the effect of a mixture of two monoclonal antibodies against non‐overlapping epitopes of HER 2 was investigated with respect to localization and stability of HER 2. Individual antibodies had limited effect, but the combination of antibodies induced internalization and degradation of HER 2 by multiple endocytic pathways. In addition, HER 2 was phosphorylated and ubiquitinated upon incubation with the antibody combination, and the HER 2 kinase activity was found to be instrumental in antibody‐induced HER 2 down‐regulation.

The maritime expansion of Scandinavian populations during the Viking Age (about ad  750–1050) was a far-flung transformation in world history 1 , 2 . Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent. Ancient DNA analyses reveal that Viking Age migrations from Scandinavia resulted in differential influxes of ancestry to different parts of Europe, and the increased presence of non-local ancestry within Scandinavia.