Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. APPROACH AND RESULTS: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). CONCLUSIONS: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.

Identification and characterization of diverse groups of endogenous retroviruses in felids.

BACKGROUND: Endogenous retroviruses (ERVs) are genetic elements with a retroviral origin that are integrated into vertebrate genomes. In felids (Mammalia, Carnivora, Felidae), ERVs have been described mostly in the domestic cat, and only rarely in wild species. To gain insight into the origins and evolutionary dynamics of endogenous retroviruses in felids, we have identified and characterized partial pro/pol ERV sequences from eight Neotropical wild cat species, belonging to three distinct lineages of Felidae. We also compared them with publicly available genomic sequences of Felis catus and Panthera tigris, as well as with representatives of other vertebrate groups, and performed phylogenetic and molecular dating analyses to investigate the pattern and timing of diversification of these retroviral elements. RESULTS: We identified a high diversity of ERVs in the sampled felids, with a predominance of Gammaretrovirus-related sequences, including class I ERVs. Our data indicate that the identified ERVs arose from at least eleven horizontal interordinal transmissions from other mammals. Furthermore, we estimated that the majority of the Gamma-like integrations took place during the diversification of modern felids. Finally, our phylogenetic analyses indicate the presence of a genetically divergent group of sequences whose position in our phylogenetic tree was difficult to establish confidently relative to known retroviruses, and another lineage identified as ERVs belonging to class II. CONCLUSIONS: Retroviruses have circulated in felids along with their evolution. The majority of the deep clades of ERVs exist since the primary divergence of felids' base and cluster with retroviruses of divergent mammalian lineages, suggesting horizontal interordinal transmission. Our findings highlight the importance of additional studies on the role of ERVs in the genome landscaping of other carnivore species.

Postoperative Pain Following Root Canal Instrumentation Using ProTaper Next or Reciproc in Asymptomatic Molars: A Randomized Controlled Single-Blind Clinical Trial.

Aim: The development of postoperative pain following root canal instrumentation may impair patient's comfort and undermine their trust in the dentist. This study assessed the effect of root canal instrumentation techniques (rotary (PTN; ProTaper Next®) and reciprocating (R; Reciproc®)) on the postoperative pain intensity (primary outcome) and tenderness on biting (secondary outcome) of patients' asymptomatic molars. Methodology: This study protocol was registered with ReBec-WHO (U1111-1182-2800). From a pool of 112 patients evaluated for eligibility (healthy adults (≤18 years old)), with a single asymptomatic molar (maxillary or mandibular) indicated for root canal treatment, diagnosed with asymptomatic irreversible pulpitis (including chronic hyperplastic pulpitis), 75 were randomly allocated in similar proportions to receive the intervention (two-appointment root canal therapy) in either the PTN or R group. The allocated procedures were performed using standardized protocols. Participants (blinded to the instrumentation technique) rated their pain intensity at 6, 12 and 24 h and from day 2 to day 7 following the root canal instrumentation appointment using a VAS and an NRS; the ibuprofen tablets taken and the presence of tenderness on biting were recorded. The instrumentation time was registered. Univariate and multivariate statistics measured the effect of independent variables on the outcomes. Results: From the 75 patients allocated, 8 patients (4 from each group) were lost; in total, 33 patients were analyzed in the PTN group and 34 in the R group. The frequencies of postoperative pain (p > 0.05) and tenderness on biting (p > 0.05) were similar between groups. The medication intake (mean of 1.31 tablets) and the time of instrumentation (approximately 11 min) were similar between groups. Conclusion: ProTaper Next and Reciproc® caused a slight risk of tenderness on biting and contributed to similar self-reported postoperative pain (low intensity) up to 7 days following root canal shaping.

Molecular phylogeny and biogeography of the eastern Tapaculos (Aves: Rhinocryptidae: Scytalopus, Eleoscytalopus): cryptic diversification in Brazilian Atlantic Forest.

Scytalopus and the recently erected Eleoscytalopus are among the Neotropical groups of birds whose taxonomy is most difficult to resolve given their very conservative morphology. We investigated the phylogeny and species limits of Eleoscytalopus and the eastern Scytalopus using two mitochondrial genes and two nuclear introns of multiple individuals from all species of these groups. The eastern Scytalopus are separated in three well defined clades also supported by morphological or vocal characteristics, although the relationships between these clades could not be resolved. We found several allopatric and very divergent lineages in these genera whose characteristics are consistent with species-level divergence, especially in S.speluncae. The great divergence between E. psychopompus and its sister species supports the former as a valid species. Our results corroborate the importance of the Bahia refuge as an avian center of endemism.

Hidden generic diversity in Neotropical birds: molecular and anatomical data support a new genus for the "Scytalopus"indigoticus species-group (Aves: Rhinocryptidae).

The genus Scytalopus is a species-rich and taxonomically complicated component of the Neotropical avian family Rhinocryptidae. Probably because Scytalopus is a superficially uniform assemblage, its monophyly has not been seriously questioned. We investigated phylogenetic relationships of a representative set of species in the genus using nuclear and mitochondrial DNA sequences as well as anatomical data, and provided the first test of its presumed monophyly by including in the analyses its hypothesized closest relatives (the genera Myornis, Eugralla, and Merulaxis) as well as most rhinocryptid genera. We found strong support for the paraphyly of the genus Scytalopus, with the Scytalopus indigoticus species-group forming a clade with Merulaxis. A well-supported clade including the genera Eugralla, Myornis, and the remaining Scytalopus was also recovered. Because these results were recovered independently and with strong support using mitochondrial and nuclear data, and were entirely consistent with anatomical data, we erect a new genus for the S.indigoticus species-group. These findings illustrate the importance of formally testing hypotheses of monophyly even for well-accepted groups of Neotropical birds.

Characterization of pantropic canine coronavirus from Brazil.

Characterization of canine coronavirus (CCoV) strains currently in circulation is essential for understanding viral evolution. The aim of this study was to determine the presence of pantropic CCoV type IIa in tissue samples from five puppies that died in Southern Brazil as a result of severe gastroenteritis. Reverse-transcriptase PCR was used to generate amplicons for sequence analysis. Phylogenetic analysis of the CCoV-IIa strains indicated that they were similar to those found in other countries, suggesting a common ancestor of these Brazilian isolates. This is the first report of pantropic CCoV-II in puppies from Latin America and our findings highlight that CCoV should be included as a differential diagnosis when dogs present with clinical signs and lesions typically seen with canine parvovirus infection.