Leiomyosarcoma Arising from the Blind End of a Bifid Renal Pelvis

Sarcoma of the kidney is a rare condition. Leiomyosarcoma is the most common of the kidney sarcomas. Renal leiomyosarcoma usually originates from the smooth muscle layers of the kidney, for example, the renal capsule and renal vessels. Renal pelvis neoplasms, however, are primarily transitional cell carcinomas, and renal pelvis leiomyosarcomas are extremely uncommon. Renal pelvis leiomyosarcoma has never been reported in Korea. Moreover, no more than 10 cases have been reported internationally. However, none of these were associated with kidney abnormalities. Here we describe a case of leiomyosarcoma that originated from the blind end of a bifid renal pelvis

Serial Measurement of WT1 Expression and Decrement Ratio Until Hematopoietic Cell Transplantation as a Marker of Residual Disease in Patients with Cytogenetically Normal Acute Myelogenous Leukemia

AbstractUsing real-time quantitative PCR, we monitored Wilms tumor gene 1 (WT1) expression from diagnosis to hematopoietic stem cell transplantation (HSCT) in adult patients with cytogenetically normal acute myelogenous leukemia (CN-AML) and FLT3-ITD and NPM1 mutations. The values at diagnosis were evaluated in 104 patients. Data collected after induction chemotherapy were available for all patients, but only 68 patients were treated with HSCT. Significant WT1 expression cut-offs were determined by receiver operation characteristic curve analysis, and rates of overall survival (OS) and disease-free survival (DFS) were estimated. WT1 decrement ratios (DR) at postinduction chemotherapy and at pre- and post-HSCT compared with the diagnostic level were calculated. Higher WT1 expression at diagnosis, postinduction chemotherapy, and pre-HSCT showed inferior OS (P = .015, <.001, and .002) and DFS (P = .006, <.001, and .003). The cut-offs were determined at the median for diagnostic WT1 expression and at the 25% level from the top for other time points excluding post-HSCT. The WT1 DR ≥ 1-log after induction chemotherapy showed superior OS and DFS (P = .009 and .002) and WT1 DR ≥ 1-log preceding HSCT also showed superior OS and DFS (P = .009 and .003). Results of WT1 DR were consistently applicable in each subgroup with higher (≥1.0) and lower (<1.0) WT1 expression at diagnosis and also in NPM1-wild-type/FLT3-ITD–negative CN-AML. The WT1 DR therefore predicted survival outcomes after HSCT more accurately than did the diagnostic WT1 expression. WT1 expression may serve as a reliable marker for residual disease and WT1 DR as a prognostic indicator, particularly in NPM1-wild-type/FLT3-ITD–negative CN-AML. These measures may be applied throughout the course of treatment and even after HSCT

The Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz (RODIN) Trial: Protocol for a Double-Blinded Clinical Trial of Nelonemdaz in Patients with Hyperacute Ischemic Stroke and Endovascular Thrombectomy

Background and Purpose Nelonemdaz (Neu2000) has both selective antagonism against 2B subunit of N-methyl-D-aspartate receptor and antioxidant activity. This drug provides sufficient evidence of neuroprotection in acute cerebral ischemia/reperfusion models. This phase III trial aims to determine this effect in patients. Design The Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz is a multicenter, double-blinded clinical trial. A total of 496 patients will be randomly assigned into the nelonemdaz (a total of 5,250 mg divided by 10 times for 5 days) and placebo groups. Patients will be included if they have an acute ischemic stroke (National Institutes of Health Stroke Scale score ≥8) caused by intracranial large vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score ≥4), and if they are expected to undergo endovascular thrombectomy within 12 hours after stroke onset. Endpoints The primary endpoint is a favorable shift in the modified Rankin Scale (mRS) score at 90 days after the first dose of drug. The data will be analyzed by the Cochran–Mantel–Haenszel shift test. The secondary endpoints include functional independence (mRS 0–2) at 35 and 90 days, the favorable shift of mRS at 35 days, the proportion of mRS 0 at 35 and 90 days, and the occurrence rates of symptomatic intracranial hemorrhage within 7 days. Conclusion This trial will clarify the efficacy and safety of nelonemdaz in patients with acute ischemic stroke and endovascular thrombectomy. This study has been registered at ClinicalTrials. gov (NCT05041010)

Consensus Subtypes of Hepatocellular Carcinoma Associated With Clinical Outcomes and Genomic Phenotypes

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies

Consensus Subtypes of Hepatocellular Carcinoma Associated With Clinical Outcomes and Genomic Phenotypes

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies

Generation of double knockout cattle via CRISPR-Cas9 ribonucleoprotein (RNP) electroporation

Background Genome editing has been considered as powerful tool in agricultural fields. However, genome editing progress in cattle has not been fast as in other mammal species, for some disadvantages including long gestational periods, single pregnancy, and high raising cost. Furthermore, technically demanding methods such as microinjection and somatic cell nuclear transfer (SCNT) are needed for gene editing in cattle. In this point of view, electroporation in embryos has been risen as an alternative. Results First, editing efficiency of our electroporation methods were tested for embryos. Presence of mutation on embryo was confirmed by T7E1 assay. With first combination, mutation rates for MSTN and PRNP were 57.6% ± 13.7% and 54.6% ± 13.5%, respectively. In case of MSTN/BLG, mutation rates were 83.9% ± 23.6% for MSTN, 84.5% ± 18.0% for BLG. Afterwards, the double-KO embryos were transferred to surrogates and mutation rate was identified in resultant calves by targeted deep sequencing. Thirteen recipients were transferred for MSTN/PRNP, 4 calves were delivered, and one calf underwent an induction for double KO. Ten surrogates were given double-KO embryos for MSTN/BLG, and four of the six calves that were born had mutations in both genes. Conclusions These data demonstrated that production of genome edited cattle via electroporation of RNP could be effectively applied. Finally, MSTN and PRNP from beef cattle and MSTN and BLG from dairy cattle have been born and they will be valuable resources for future precision breeding.This study was financially supported by the National Research Foundation of Korea (NRF-2021R1A5A1033157 for SRC program: 382 Comparative medicine Disease Research Center; NRF-2021R1F1A105195313), the Research Institute of Veterinary Science, the BK21 Four for Future Veterinary Medicine Leading Education and Research Center, and a Seoul National University (SNU) grant (#550e2020005

Ginkgo biloba extract (GbE) enhances the anti-atherogenic effect of cilostazol by inhibiting ROS generation

In this study, the synergistic effect of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) and Ginkgo biloba extract (GbE) was examined in apolipoprotein E (ApoE) null mice. Co-treatment with GbE and cilostazol synergistically decreased reactive oxygen species (ROS) production in ApoE null mice fed a high-fat diet. Co-treatment resulted in a significantly decreased atherosclerotic lesion area compared to untreated ApoE mice. The inflammatory cytokines and adhesion molecules such as monocyte chemoattractant-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and VCAM-1 which can initiate atherosclerosis were significantly reduced by the co-treatment of cilostazol with GbE. Further, the infiltration of macrophages into the intima was decreased by co-treatment. These results suggest that co-treatment of GbE with cilostazol has a more potent anti-atherosclerotic effect than treatment with cilostazol alone in hyperlipidemic ApoE null mice and could be a valuable therapeutic strategy for the treatment of atherosclerosis

Adaptive laboratory evolution of Escherichia coli lacking cellular byproduct formation for enhanced acetate utilization through compensatory ATP consumption

Acetate has attracted great attention as a carbon source to develop economically feasible bioprocesses for sustainable bioproducts. Acetate is a less-preferred carbon source and a well-known growth inhibitor of Escherichia coli. In this study, we carried out adaptive laboratory evolution of an E. coli strain lacking four genes (adhE, pta, ldhA, and frdA) involved in acetyl-CoA consumption, allowing the efficient utilization of acetate as its sole carbon and energy source. Four genomic mutations were found in the evolved strain through whole-genome sequencing, and two major mutations (in cspC and patZ) mainly contributed to efficient utilization of acetate and tolerance to acetate. Transcriptomic reprogramming was examined by analyzing the genome-wide transcriptome with different carbon sources. The evolved strain showed high levels of intracellular ATP by upregulation of genes involved in NADH and ATP biosynthesis, which facilitated the production of enhanced green fluorescent protein, mevalonate, and n-butanol using acetate alone. This new strain, given its high acetate tolerance and high ATP levels, has potential as a starting host for cell factories targeting the production of acetyl-CoA-derived products from acetate or of products requiring high ATP levels