Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Association of interleukin-6 polymorphisms with obesity or metabolic traits in young Mexican-Americans.

Objective: The objective of the study is to investigate the association of interleukin-6 (IL6) promoter single-nucleotide polymorphisms rs1800797 (-597 G/A) and rs1800796 (-572 G/C) with obesity or metabolic syndrome in Mexican-Americans. Methods: The rs1800797 and rs1800796 single-nucleotide polymorphisms were genotyped in Mexican-Americans (n = 437) from South Texas, and results were correlated with measures of obesity and metabolic syndrome including body mass index, waist circumference, blood pressure, cholesterol, triglycerides, glucose, liver enzymes, plasma IL6 and high-sensitive C-reactive protein (hs-CRP). Results: Significant associations were found for the rs1800796 variant with increased waist circumference, insulin resistance, lower IL6 levels and higher hs-CRP levels. The rs1800797 variant showed no associations with metabolic traits but was associated with higher IL6 levels and lower hs-CRP levels. Conclusions: Findings in this study support the anti-inflammatory, anti-obesity and glucose homeostatic roles of IL6 in Mexican-American youth.

Likely multiple origins of a diploid hybrid sunflower species.

The recurrent origin of diploid hybrid species is theoretically improbable because of the enormous diversity of hybrid genotypes generated by recombination. Recent greenhouse experiments, however, indicate that the genomic composition of hybrid lineages is shaped in part by deterministic forces, and that recurrent diploid hybrid speciation may be more feasible than previously believed. Here we use patterns of variation from chloroplast DNA (cpDNA), nuclear microsatellite loci, cross-viability and chromosome structure to assess whether a well-characterized diploid hybrid sunflower species, Helianthus anomalus, was derived on multiple occasions from its parental species, H. annuus and H. petiolaris. Chloroplast DNA and crossability data were most consistent with a scenario in which H. anomalus arose three times: three different H. anomalus fertility groups were discovered, each with a unique cpDNA haplotype. In contrast, there was no clear signature of multiple, independent origins from the microsatellite loci. Given the age of H. anomalus (> 100 000 years bp), it may be that microsatellite evidence for recurrent speciation has been eroded by mutation and gene flow through pollen.

Transgressive character expression in a hybrid sunflower species.

Diploid hybrid lineages often are ecologically distinct from their parental species. However, it is unclear whether this niche divergence is typically achieved via hybrid intermediacy, a mixture of parental traits, and/or the evolution of extreme (transgressive) morphological and ecophysiological features. Here we compare an extensively studied hybrid sunflower species, Helianthus anomalus, with its putative parents, H. annuus and H. petiolaris, for 41 morphological and 12 ecophysiological traits. Helianthus anomalus was morphologically intermediate for one trait (2.4%), parental-like for 23 traits (56.1%), and transgressive for 17 traits (41.5%). For ecophysiological traits, H. anomalus was not significantly different from one or both parents for nine traits (75%), and was transgressive for the remaining three (25%). Thus, H. anomalus appears to be a mosaic of parental-like and transgressive phenotypes. Although the fitness effects of the transgressive characters are not yet known, many of these characters are consistent with adaptations reported for other sand dune plants. Genetic studies are currently underway to ascertain whether these extreme characters arose as a direct byproduct of hybridization or whether they evolved via mutational divergence.

Systematic affinities of Rhizophoraceae and Anisophylleaceae, and intergeneric relationships within Rhizophoraceae, based on chloroplast DNA, nuclear ribosomal DNA, and morphology.

A cladistic analysis of sequences from the chloroplast gene rbcL was used to determine the systematic affinities of Rhizophoraceae and Anisophylleaceae. This analysis rejects close relationships of Rhizophoraceae with Celastraceae or Elaeocarpaceae, suggested previously, and identifies Erythroxylaceae as sister group within the Malpighiales, supported by several morphological and anatomical characters. Our molecular results also indicate that Anisophylleaceae are nested within Cucurbitales. Although this placement is novel, this affinity is also well supported by shared morphological characters. Tribal and generic relationships within Rhizophoraceae are evaluated with a combination of six molecular data sets (rbcL, atpB-rbcL intergenic spacer, trnL-trnF intergenic spacer, ITS1, ITS2, and 5.8S) and a morphological data set. These relationships are compared with results from previous morphological cladistic analyses. Against the background of the molecular results, we briefly discuss the evolution of morphological characters traditionally used for tribal subdivision as well as characters presumably significant for adaptation to mangrove habitats, namely, aerial stilt roots and vivipary.