patient-derived-tumor-explants-as-live-preclinical-platform-for

Patient-Derived Tumor Explants As a "Live" Preclinical Platform for Predicting Drug Resistance in Patients

An understanding of drug resistance and the development of novel strategies to sensitize highly resistant cancers rely on the availability of suitable ...

University of Leicester

A short period of isolated normothermic perfusion (NP) can be used to improve the condition of the kidney after periods of warm and cold ischemic injury. However, the mechanisms underlying this beneficial effect have not been determined.

The conditioning effect of ex vivo normothermic perfusion in an experimental kidney model.

Ex vivo normothermic perfusion (EVNP) can reverse some of the detrimental effects of ischemic injury. However, in kidneys with warm and cold ischemic injury the optimal perfusion pressure remains undetermined. The aim of this study was to evaluate the effects of two different arterial pressures during EVNP.

The effects of arterial pressure during normothermic kidney perfusion.

Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic guanosine 3',5'-monophosphate (cGMP) and therefore may be useful in reducing the detrimental effects of ischemia-reperfusion (I/R) injury. The aim of this study was to assess the effects of the phosphodiesterase-5 inhibitor sildenafil, on I/R injury in a porcine model of donation after circulatory death kidney transplantation.

Sildenafil citrate in a donation after circulatory death experimental model of renal ischemia-reperfusion injury.

Remote renal ischemia-reperfusion injury (IRI) following infra-renal aortic occlusion leads to acute kidney injury and systemic inflammation. Hydrogen sulfide is a mediator of IRI and can ameliorate tissue injury in many organ systems. Its role in vascular surgery has yet to be established. We assessed the role of hydrogen sulfide in a rodent model of aortic occlusion.

Hydrogen sulfide reduces inflammation following abdominal aortic occlusion in rats.

Calcineurin inhibitors have significant nephrotoxic side effects, which can exacerbate ischemia-reperfusion injury in renal transplantation. Novel therapeutic agents such as hydrogen sulphide (H₂S) may reduce these harmful effects. This study investigated the effects of H₂S on cyclosporine (CsA) induced nephrotoxicity.

Hydrogen sulphide as a novel therapy to ameliorate cyclosporine nephrotoxicity.

There is a critical need to better preserve isolated organs before transplantation. We developed a novel nonerythropoiesis cyclic helix B peptide (CHBP) derived from erythropoietin, which has potent tissue protection and prolonged serum stability. The renoprotection and potential mechanism of CHBP were evaluated in a kidney preservation model.

Cyclic Helix B Peptide in Preservation Solution and Autologous Blood Perfusate Ameliorates Ischemia-Reperfusion Injury in Isolated Porcine Kidneys.

Ex vivo perfusion (EVP) is a novel method of preservation. However, optimal perfusion conditions remain undetermined. Reducing the temperature of the perfusate to subnormothermia may be beneficial during EVP and improve early graft function. The aim of this study was to investigate whether subnormothermia would influence the conditioning effect of EVP when compared with normothermic perfusion, and standard cold static storage (CS).

Lowering Perfusate Temperature From 37°C to 32°C Diminishes Function in a Porcine Model of Ex Vivo Kidney Perfusion.

Preclinical models that can accurately predict outcomes in the clinic are much sought after in the field of cancer drug discovery and development. Existing models such as organoids and patient-derived xenografts have many advantages, but they suffer from the drawback of not contextually preserving human tumour architecture. This is a particular problem for the preclinical testing of immunotherapies, as these agents require an intact tumour human-specific microenvironment for them to be effective. In this review, we explore the potential of patient-derived explants (PDEs) for fulfilling this need. PDEs involve the ex vivo culture of fragments of freshly resected human tumours that retain the histological features of original tumours. PDE methodology for anti-cancer drug testing has been in existence for many years, but the platform has not been widely adopted in translational research facilities, despite strong evidence for its clinical predictivity. By modifying PDE endpoint analysis to include the spatial profiling of key biomarkers by using multispectral imaging, we argue that PDEs offer many advantages, including the ability to correlate drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. As such, PDEs are a powerful model of choice for cancer drug and biomarker discovery programmes.

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery.

 Kidneys from donation after circulatory death (DCD) are more likely to be declined for transplantation compared with kidneys from donation after brain death (DBD). The aim of this study was to evaluate characteristics in the biopsies of human DCD and DBD kidneys that were declined for transplantation in order to rescue more DCD kidneys.  Sixty kidney donors (DCD = 36, DBD = 24) were recruited into the study and assessed using donor demographics. Kidney biopsies taken post cold storage were also evaluated for histological damage, inflammation (myeloperoxidase, MPO), von Willebrand factor (vWF) expression, complement 4d (C4d) deposition and complement 3 (C3) activation using H&E and immunohistochemistry staining, and Western blotting.  More DBD donors (16/24) had a history of hypertension compared with DCDs (8/36,  = 0.001). The mean warm ischemic time in the DCD kidneys was 12.9 ± 3.9 min. The mean cold ischemic time was not significantly different between the two groups of kidney donors (DBD 33.3 ± 16.7 vs. DCD 28.6 ± 14.1 h,  > 0.05). The score of histological damage and MPO, as well as the reactivity of vWF, C4d and C3, varied between kidneys, but there was no significant difference between the two donor types ( > 0.05). However, vWF reactivity might be an early indicator for loss of tissue integrity, while C4d deposition and activated C3 might be better predictors for histological damage.  Similar characteristics of DCD were shown in comparison with DBD kidneys. Importantly, the additional warm ischemic time in DCD appeared to have no further detectable adverse effects on tissue injury, inflammation and complement activation. vWF, C4d and C3 might be potential biomarkers facilitating the evaluation of donor kidneys.

Meeta Patel

Leicester Cancer Research Center

University of Leicester

Patient-Derived Tumor Explants As a "Live" Preclinical Platform for Predicting Drug Resistance in Patients