Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets

Probing MSSM Higgs Sector with Explicit CP Violation at a Photon Linear Collider

The CP properties of Higgs bosons can be probed through their s-channel resonance productions via photon-photon collisions by use of circularly and/or linearly polarized backscattered laser photons at a TeV-scale linear e^+ e^- collider. Exploiting this powerful tool, we investigate in detail the Higgs sector of the minimal supersymmetric Standard Model with explicit CP violation.Comment: 18 pages, 5 figures. Some comments added and typos corrected. To appear in Phys. Rev.

MSSM Higgs-Boson Production at Hadron Colliders with Explicit CP Violation

Gluon fusion is the main production mechanism for Higgs bosons with masses up to several hundred GeV in $pp$ collisions at the CERN Large Hadron Collider. We investigate the effects of the CP-violating phases on the fusion process including both the sfermion-loop contributions and the one-loop induced CP-violating scalar-pseudoscalar mixing in the minimal supersymmetric standard model. With a universal trilinear parameter assumed, every physical observable involves only the sum of the phases of the universal trilinear parameter $A$ and the higgsino mass parameter $\mu$. The phase affects the lightest Higgs-boson production rate significantly through the neutral Higgs-boson mixing and, for the masses around the lightest stop-pair threshold, it also changes the production rate of the heavy Higgs bosons significantly through both the stop and sbottom loops and the neutral Higgs-boson mixing.Comment: 28 pages, 8 figures. Some references and comments added. Typos corrected. To appear in Phys. Rev.

Image-based goal-oriented adaptive isogeometric analysis with application to the micro-mechanical modeling of trabecular bone

Isogeometric analysis (IGA) of geometrically complex three-dimensional objects is possible when used in combination with the Finite Cell method (FCM). In this contribution we propose a computational methodology to automatically analyze the effective elastic properties of scan-based volumetric objects of arbitrary geometric and topological complexity. The first step is the reconstruction of a smooth geometry from scan-based voxel data using a B-spline level set function. The second step is a goal-oriented adaptive isogeometric linear elastic analysis. Elements are selected for refinement using dual-weighted residual shape function indicators, and hierarchical splines are employed to construct locally refined spline spaces. The proposed methodology is studied in detail for various numerical test cases, including the computation of the effective Young's modulus of a trabecular bone micro-structure reproduced from μCT-scan data

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID