Tumor Burden Affects Efficacy of Combination Immunotherapy [Research Watch]

Combined CTLA4 and PD-L1 blockade hinders antitumor immunity in patients with low tumor burden.

http://bit.ly/2DJ8x4d

Chromosome-Wide Evolution and Sex Determination in the Three-Sexed Nematode Auanema rhodensis

Trioecy, a mating system in which males, females and hermaphrodites co-exist, is a useful system to investigate the origin and maintenance of alternative mating In the trioecious nematode Auanema rhodensis, males have one X chromosome (XO), whereas females and hermaphrodites have two (XX). The female versus hermaphrodite sex determination mechanisms have remained elusive. In this study, RNA-seq analyses show a 20% difference between the L2 hermaphrodite and female gene expression profiles. RNAi experiments targeting the DM (doublesex/mab-3) domain transcription factor dmd-10/11 suggest that the hermaphrodite sexual fate requires the upregulation of this gene. The genetic linkage map (GLM) shows that there is chromosome-wide heterozygosity for the X chromosome in F2 hermaphrodite-derived lines originated from crosses between two parental inbred strains. These results confirm the lack of recombination of the X chromosome in hermaphrodites, as previously reported. We also describe conserved chromosome elements (Nigon elements), which have been mostly maintained throughout the evolution of Rhabditina nematodes. The seven-chromosome karyotype of A. rhodensis, instead of the typical six found in other rhabditine species, derives from fusion/rearrangements events involving three Nigon elements. The A. rhodensis X chromosome is the smallest and most polymorphic with the least proportion of conserved genes. This may reflect its atypical mode of father-to-son transmission and its lack of recombination in hermaphrodites and males. In conclusion, this study provides a framework for studying the evolution of chromosomes in rhabditine nematodes, as well as possible mechanisms for the sex determination in a three-sexed species.

http://bit.ly/2X6vQhm

The m6A-Binding Protein YTHDF1 Mediates Immune Evasion [Research Watch]

Loss of the mRNA m⁶A-binding protein YTHDF1 in dendritic cells enhances antitumor immunity.

http://bit.ly/2DHMbQJ

TP53 Mutations Are Immunogenic in Epithelial Cancer [Research Watch]

Mutant p53-specific T cells were isolated from patients with metastatic epithelial cancers.

http://bit.ly/2SE1Jiw

Bacterial Mix Enhances Immunotherapy Response [News in Brief]

Anti–PD-1, anti-CTLA4 therapies work better in mice after inoculation of 11 microbial strains.

http://bit.ly/2SFj2A2

Targeting Alterations in the RAF-MEK Pathway [Review]

The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF^V600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specific RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.

Significance: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.

http://bit.ly/2DO5M1Q

Cell Growth-Induced Dilution of Cytoplasm Contributes to Senescence [Research Watch]

Large cell size affects multiple cellular processes, inhibits proliferation, and accelerates aging.

http://bit.ly/2SADD8x