5 research outputs found
Unusual Echocardiographic Diagnosis of a Metastatic Thrombus - A Case Report
No full textRenal cell carcinoma has high propensity for intravascular and lymphatic spread. In one percent of such cases, tumor can reach up to the right atrium. This case reports the postoperative tumor embolization in a patient with renal cell carcinoma. An elderly female underwent a left radical nephrectomy and inferior vena cava (IVC) thrombectomy. She developed atrial fibrillation on the sixth postoperative day following the surgery in the postoperative unit. A bedside transthoracic echocardiogram detected a migrating echo dense structure moving across the tricuspid valve. Following this, she underwent an urgent right atriotomy and extraction of the tumor thrombus through cardiopulmonary bypass. The occurrence of atrial fibrillation in this patient with renal cell cancer in the postoperative period could have possibly been trigerred by a tumor thrombus in the right atrium
PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kα inhibition
No full textPIK3CA, the gene encoding the alpha isoform of PI3K (PI3Kα), is frequently mutated and oncogenic in breast cancer. PI3Kα inhibitors are in clinical development and despite promising early clinical activity, primary and acquired resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Kα inhibitors drives resistance to these agents. However, the underlying mechanisms that mediate this phenotype are not fully understood. Here we show that in cancer cells resistant to PI3Kα inhibition, PDK1 blockade restores sensitivity to these therapies. SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity and cell survival through direct phosphorylation and inhibition of TSC2. Targeting either PDK1 or SGK1 prevents mTORC1 activation and restores the antitumoral effects of PI3Kα inhibition in resistant cancer cells
Expanding the DNA editing toolbox: novel lambda integrase variants targeting microalgal and human genome sequences
No full textRecombinase enzymes are extremely efficient at integrating very large DNA fragments into target genomes. However, intrinsic sequence specificities curtail their use to DNA sequences with sufficient homology to endogenous target motifs. Extensive engineering is therefore required to broaden applicability and robustness. Here, we describe the directed evolution of novel lambda integrase variants capable of editing exogenous target sequences identified in the diatom Phaeodactylum tricornutum and the algae Nannochloropsis oceanica. These microorganisms hold great promise as conduits for green biomanufacturing and carbon sequestration. The evolved enzyme variants show >1000-fold switch in specificity towards the non-natural target sites when assayed in vitro. A single-copy target motif in the human genome with homology to the Nannochloropsis oceanica site can also be efficiently targeted using an engineered integrase, both in vitro and in human cells. The developed integrase variants represent useful additions to the DNA editing toolbox, with particular application for targeted genomic insertion of large DNA cargos.National Research Foundation (NRF)Published versionThis work was supported through a grant from the National Research Foundation-Competitive Research Programme, Singapore to PD (NRF-CRP21-2018-0002). The funder provided support in the form of salaries for authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section There was no additional external funding received for this study
High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> breast cancer
No full textCDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n?=?37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n?=?89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.© 2022. The Author(s)
