A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.

Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.

Quality of Life after Pars Plana Vitrectomy, Scleral Buckle, or Pneumatic Retinopexy for Rhegmatogenous Retinal Detachment: A Meta-Analysis.

PURPOSE: Comparisons of the surgical and anatomic results of rhegmatogenous retinal detachment surgery have been investigated previously. A systematic evaluation of the available evidence comparing quality of life outcomes of either pars plana vitrectomy, scleral buckling, or pneumatic retinopexy has not been evaluated to date. This article analyzes whether pars plana vitrectomy, scleral buckling, or pneumatic retinopexy for the treatment of rhegmatogenous retinal detachment results in differing quality of life outcomes. METHODS: In February of 2022, a comprehensive search of MEDLINE, EMBASE, CINHAL, and Cochrane Library was conducted for studies on patients treated surgically for rhegmatogenous retinal detachment and included follow-up measurements of quality of life outcomes. Meta-analysis was completed using STATA v. 14.0. The main outcomes of interest were the mean vision-related quality of life score (VRQOL) and SD of VRQOL of each type of surgical procedure. RESULTS: In this systematic review of 13 distinct trials including follow-up of patient quality of life after rhegmatogenous retinal detachment surgery (n = 1063), a better correlation was found between higher quality of life outcomes with scleral buckling than with pars plana vitrectomy (SMD = 0.62, CI: [0.31, 0.93]). There was also no signficant difference in quality of life outcomes between pneumatic retinopexy and pars plana vitrectomy (SMD = 0.08, CI: [-0.07, 0.22]). CONCLUSIONS: Scleral buckling results in better quality of life outcomes for patients when compared to pars plana vitrectomy. Pneumatic retinopexy did not show a difference in quality of life outcomes compared to pars plana vitrectomy.

Sortilin-Driven Cancer Secretome Enhances Tumorigenic Properties of Hepatocellular Carcinoma via de Novo Lipogenesis.

A growing body of evidence suggests de novo lipogenesis as a key metabolic pathway adopted by cancers to fuel tumorigenic processes. While increased de novo lipogenesis has also been reported in hepatocellular carcinoma (HCC), understanding on molecular mechanisms driving de novo lipogenesis remains limited. In the present study, the functional role of sortilin, a member of the vacuolar protein sorting 10 protein receptor family, in HCC was investigated. Sortilin was overexpressed in HCC and was associated with poorer survival outcome. In functional studies, sortilin-overexpressing cells conferred tumorigenic phenotypes, namely, self-renewal and metastatic potential, of HCC cells via the cancer secretome. Proteomic profiling highlighted fatty acid metabolism as a potential molecular pathway associated with sortilin-driven cancer secretome. This finding was validated by the increased lipid content and expression of fatty acid synthase (FASN) in HCC cells treated with conditioned medium collected from sortilin-overexpressing cells. The enhanced tumorigenic properties endowed by sortilin-driven cancer secretome were partly abrogated by co-administration of FASN inhibitor C75. Further mechanistic dissection suggested protein stabilization by post-translational modification with O-GlcNAcylation as a major mechanism leading to augmented FASN expression. In conclusion, the present study uncovered the role of sortilin in hepatocarcinogenesis via modulation of the cancer secretome and deregulated lipid metabolism.

Mechanism of Rad26-assisted rescue of stalled RNA polymerase II in transcription-coupled repair.

Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while triggering excision of others is incompletely understood. Here we build structural models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in nucleotide-free and bound states. This enables simulations and graph-theoretical analyses to define partitioning of this complex into dynamic communities and delineate how its structural elements function together to remodel DNA. We identify an allosteric pathway coupling motions of the Rad26 ATPase modules to changes in RNA polymerase and DNA to unveil a structural mechanism for CSB-assisted progression past less bulky lesions. Our models allow functional interpretation of the effects of Cockayne syndrome disease mutations.