LiverMap pipeline for 3D imaging of human liver reveals volumetric spatial dysregulation of cirrhotic vasculobiliary architecture.

The liver contains an intricate microstructure that is critical for liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, 2D histopathology - the gold standard for pathological understanding of many liver diseases - can misrepresent or leave gaps in our understanding of complex 3D structural features.

Label-free, real-time monitoring of cytochrome C drug responses in microdissected tumor biopsies with a multi-well aptasensor platform.

Functional assays on intact tumor biopsies can complement genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key therapeutic response determinants, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Most of these assays rely on fluorescent labeling, a semiquantitative method best suited for single-time-point assays or labor-intensive immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase () mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis.

Low-Cost Robotic Manipulation of Live Microtissues for Cancer Drug Testing.

Unlabelled: The scarcity of human biopsies available for drug testing is a paramount challenge for developing new therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible.

Microdissected tumor cuboids: a microscale cancer model for large-scale testing that retains a complex tumor microenvironment.

To bridge the gap between bench and bedside, there is a need for more faithful models of human cancers that can recapitulate key features of the human tumor microenvironment (TME) and simultaneously facilitate large-scale drug tests. Our recently developed microdissection method optimizes the yield of large numbers of cuboidal microtissues (″cuboids″, ~(400 µm) ) from a tumor biopsy. Here we demonstrate that cuboids from syngeneic mouse tumor models and human tumors retain a complex TME, making them amenable for drug and immunotherapy evaluation.

Label-Free, Real-Time Monitoring of Cytochrome C Responses to Drugs in Microdissected Tumor Biopsies with a Multi-Well Aptasensor Platform.

Functional assays on intact tumor biopsies can potentially complement and extend genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key determinants of therapeutic response, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Currently, most of these assays rely on fluorescent labeling, a semi-quantitative method best suited to be a single-time-point terminal assay or labor-intensive terminal immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of increases of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity.

Organotypic Models for Functional Drug Testing of Human Cancers.

In the era of personalized oncology, there have been accelerated efforts to develop clinically relevant platforms to test drug sensitivities of individual cancers. An ideal assay will serve as a diagnostic companion to inform the oncologist of the various treatments that are sensitive and insensitive, thus improving outcome while minimizing unnecessary toxicities and costs. To date, no such platform exists for clinical use, but promising approaches are on the horizon that take advantage of improved techniques in creating human cancer models that encompass the entire tumor microenvironment, alongside technologies for assessing and analyzing tumor response.

Quantification of Hepatocellular Carcinoma Vascular Dynamics With Contrast-Enhanced Ultrasound for LI-RADS Implementation.

Objective: The aim of this study is to describe a comprehensive contrast-enhanced ultrasound (CEUS) imaging protocol and analysis method to implement CEUS LI-RADS (Liver Imaging Reporting and Data System) in a quantifiable manner. The methods that are validated with a prospective single-center study aim to simplify CEUS LI-RADS evaluation, remove observer bias, and potentially improve the sensitivity of CEUS LI-RADS.

Materials And Methods: This prospective single-center study enrolled patients with hepatocellular carcinoma (April 2021-June 2022; N = 31; mean age ± SD, 67 ± 6 years; 24 men/7 women).

Multiple Linear-Combination Security Network Coding.

In this paper, we put forward the model of multiple linear-combination security multicast network coding, where the wiretapper desires to obtain some information about a predefined set of multiple linear combinations of the source symbols by eavesdropping any one (but not more than one) channel subset up to a certain size , referred to as the . For this model, the security capacity is defined as the maximum average number of source symbols that can be securely multicast to all sink nodes for one use of the network under the linear-combination security constraint. For any security level and any linear-combination security constraint, we fully characterize the security capacity in terms of the ratio of the rank of the linear-combination security constraint to the number of source symbols.

Republication of "Percutaneous Basal Closing Wedge Osteotomy of the First Metatarsal in the Treatment of Moderate to Severe Hallux Valgus and Its Short-Term Clinical Outcomes".

Background: Although percutaneous surgery for the treatment of hallux valgus is popular in Europe, there is sparse English written literature documenting its efficacy. This study described the operative techniques using percutaneous basal closing wedge osteotomy of the first metatarsal in correction of moderate to severe hallux valgus (HV) and its short-term clinical outcomes. We postulated that satisfactory correction of hallux valgus (HV) angle, intermetatarsal (IM) angle, and patients' clinical outcomes could be achieved with this technique.

Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma.

The DNAJ-PKAc fusion kinase is a defining feature of the adolescent liver cancer fibrolamellar carcinoma (FLC). A single lesion on chromosome 19 generates this mutant kinase by creating a fused gene encoding the chaperonin binding domain of Hsp40 (DNAJ) in frame with the catalytic core of protein kinase A (PKAc). FLC tumors are notoriously resistant to standard chemotherapies.

Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms.

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer.

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

Objective: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.

Design: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells.

Response of Human Liver Tissue to Innate Immune Stimuli.

Precision-cut human liver slice cultures (PCLS) have become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) using normal and diseased liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy.

Safety of Image-Guided Treatment of the Liver with Ultrasound and Microbubbles in an in Vivo Porcine Model.

Ultrasound and microbubbles are useful for both diagnostic imaging and targeted drug delivery, making them ideal conduits for theranostic interventions. Recent reports have indicated the preclinical success of microbubble cavitation for enhancement of chemotherapy in abdominal tumors; however, there have been limited studies and variable efficacy in clinical implementation of this technique. This is likely because in contrast to the high pressures and long cycle lengths seen in successful preclinical work, current clinical implementation of microbubble cavitation for drug delivery generally involves low acoustic pressures and short cycle lengths to fit within clinical guidelines.

Protocol for tissue slice cultures from human solid tumors to study therapeutic response.

The impact of systemic therapy on the tumor microenvironment has been difficult to study in human solid tumors. Our protocol describes steps for establishing slice cultures to investigate response to chemotherapies, immunotherapies, or adoptive cell therapies. Endpoints include changes in viability, histology, live-cell imaging, and multi-omics analyses.

Hepatic artery aneurysm in the setting of focal nodular hyperplasia.

Hepatic artery aneurysms (HAA) are rare and may be seen in the setting of infection and vascular disease. Clinical presentation is variable but many are found incidentally during imaging studies. The association of HAA with focal nodular hyperplasia (FNH) is rarely reported in literature.

IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections.

Background: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution.

Glypican-3 targeted delivery of Zr and Y as a theranostic radionuclide platform for hepatocellular carcinoma.

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (Zr) and yttrium-90 (Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated.

Functional responses of resident human T cells in intact liver tissue.

The liver contains a rich mix of T cells, including activated T cells, tissue-resident memory T cells and cells undergoing apoptosis. When antigens are presented in this milieu the default result is functional tolerance. T cell tolerance in the liver could be constitutive, or it could be adaptive, in which case liver cells would become unresponsive after encountering antigen in the liver context.

Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis.

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell-specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations.

Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases.

Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment.