This work, describing siRNA targeting FXIII-B (siFXIIIB), is the first pharmacologic approach for long-acting, reversible, and targeted decrease of FXIII-A activity in vivo. It enables the study of FXIII in a wide range of disease models, including in animals not amenable to genetic FXIII knockout. FXIII is considered a therapeutic target for preventing thrombosis, and siFXIIIB overcomes limitations of current antithrombics and thrombolytics by specifically enhancing endogenous fibrinolysis.
In some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among…
Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of…
The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W-inducible isogenic cell lines and performed…
The authors show that integrins play a key role during fly hematopoiesis in regulating cell signals that control the behaviour of hematopoietic progenitors. Integrins regulate fly hematopoiesis directly, via integrin-mediated FAK signalling, and indirectly, by modulating ECM density. ECM density controls blood progenitor behaviour by influencing multiple signalling pathways, including bone morphogenetic protein and Hedgehog.
Compelling evidence has shown that LIN28b plays an important role in regulating the lineage switch of prostatic luminal epithelial cells to neuroendocrine cells. This study identifies LIN28B as a potential therapeutic target to treat therapy-induced neuroendocrine prostate cancer, a lethal subtype of therapy-resistant prostate cancers. This information will direct future strategies to design new therapeutics to treat this type of tumour.
This study not only uncovers mechanisms of diffuse large B cell lymphoma (DLBCL) treatment resistance, but also provides insight into the importance of genetic testing for DLBCL patients and demonstrates how this could be accomplished using minimally invasive analysis of circulating tumour DNA from blood samples. Screening for mutations in key resistance genes at the time of diagnosis and throughout treatment with R-CHOP may help clinicians better manage treatment strategies for DLBCL patients.
This work sheds new light on the molecular machinery that controls β-cell survival. The authors compared β-cells with four distinct genetic changes to determine the individual and combined contribution of two Bcl-2 family ‘executioner’ proteins, Bax and Bak, to β-cell death induced by the type of glucose and lipid-induced stress the β-cells experience in the development of type 2 diabetes.
The researchers employed the Oxford Nanopore PromethION long-read sequencer to re-sequence and analyze the genomes of cancer patients enrolled in BC Cancer’s Personalized OncoGenomics program, which were previously sequenced using only short-read technology. The findings of this study suggest that, for these patients, long-read sequencing may be advantageous to confirm the presence or absence of germline structural variants that may have implications for their disease.
The Cre-LoxP system, which uses a tool borrowed from viruses, is the most prevalent technology used to to delete or activate genes. Conventionally, expression of Cre in specific cells has required use of special genetically modified mice that are extremely costly and time consuming to generate. As an alternative, the authors designed and developed a novel gene therapy tool that can act as a “trojan horse” to selectively deliver Cre to beta-cells in the pancreas.