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Role of the Lymphatics in Cardiac Disease.
Cardiovascular diseases remain the largest cause of death worldwide with recent evidence increasingly attributing the development and progression of these diseases to an exacerbated inflammatory response. As a result, significant research is now focused on modifying the immune environment to prevent the disease progression. This in turn has highlighted the lymphatic system in the pathophysiology of cardiovascular diseases owing, in part, to its established function in immune cell surveillance and trafficking. In this review, we highlight the role of the cardiac lymphatic system and its potential as an immunomodulatory therapeutic target in selected cardiovascular diseases.
Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration.
Age-related macular degeneration is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of age-related macular degeneration that has the appearance the 'dry' form, or geographic atrophy. Biallelic variants in CDHR1 - a specialised protocadherin highly expressed in cone and rod photoreceptors - result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional and behavioural rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months post-injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy appears to be near complete - with morphological findings of the rescued retina not obviously different to wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry age-related macular degeneration. Accurate clinical classification is now critical as their pathogenesis and treatment are distinct.
Correction: Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2).
Correction for 'Modified minimal-size fragments of heparan sulfate as inhibitors of endosulfatase-2 (Sulf-2)' by Alice Kennett et al., Chem. Commun., 2024, 60, 436-439, https://doi.org/10.1039/D3CC02565A.
Redefining clinical practice through spatial profiling: a revolution in tissue analysis.
Spatial biology, which combines molecular biology and advanced imaging, enhances our understanding of tissue cellular organisation. Despite its potential, spatial omics encounters challenges related to data complexity, computational requirements and standardisation of analysis. In clinical applications, spatial omics has the potential to revolutionise biomarker discovery, disease stratification and personalised treatments. It can identify disease-specific cell patterns, and could help risk stratify patients for clinical trials and disease-appropriate therapies. Although there are challenges in adopting it in clinical practice, spatial omics has the potential to significantly enhance patient outcomes. In this paper, we discuss the recent evolution of spatial biology, and its potential for improving our tissue level understanding and treatment of disease, to help advance precision and effectiveness in healthcare interventions.
Early deficits in an in vitro striatal microcircuit model carrying the Parkinson's GBA-N370S mutation.
Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD.
Somatic gene mutation patterns and burden influence outcomes with enasidenib in relapsed/refractory IDH2-mutated AML
Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.
Flow Dynamics in Stented Ureter
Urinary flow is governed by the principles of fluid mechanics. Urodynamic studies have revealed the fundamental kinematics and dynamics of urinary flow in various physiological and pathological conditions, which are cornerstones for future development of diagnostic knowledge and innovative devices. There are three primary approaches to study the fluid mechanical characteristics of urinary flow: reduced order, computational, and experimental methods. Reduced-order methods exploit the disparate length scales inherent in the system to reveal the key dominant physics. Computational models can simulate fully three-dimensional, time-dependent flows in physiologically-inspired anatomical domains. Finally, experimental models provide an excellent counterpart to reduced and computational models by providing physical tests under various physiological and pathological conditions. While the interdisciplinary approaches to date have provided a wealth of insight into the fluid mechanical properties of the stented ureter, the next challenge is to develop new theoretical, computational and experimental models to capture the complex interplay between the fluid dynamics in stented ureters and biofilm/encrustation growth. Such studies will (1) enable identification of clinically relevant scenarios to improve patients’ treatment, and (2) provide physical guidelines for next-generation stent design.
A continuum model for the elongation and orientation of Von Willebrand factor with applications in arterial flow
<jats:title>Abstract</jats:title><jats:p>The blood protein Von Willebrand factor (VWF) is critical in facilitating arterial thrombosis. At pathologically high shear rates, the protein unfolds and binds to the arterial wall, enabling the rapid deposition of platelets from the blood. We present a novel continuum model for VWF dynamics in flow based on a modified viscoelastic fluid model that incorporates a single constitutive relation to describe the propensity of VWF to unfold as a function of the scalar shear rate. Using experimental data of VWF unfolding in pure shear flow, we fix the parameters for VWF’s unfolding propensity and the maximum VWF length, so that the protein is half unfolded at a shear rate of approximately <jats:inline-formula><jats:alternatives><jats:tex-math>$$5000\,\text {s}^{-1}$$</jats:tex-math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mn>5000</mml:mn> <mml:mspace /> <mml:msup> <mml:mtext>s</mml:mtext> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> </mml:mrow> </mml:math></jats:alternatives></jats:inline-formula>. We then use the theoretical model to predict VWF’s behaviour in two complex flows where experimental data are challenging to obtain: pure elongational flow and stenotic arterial flow. In pure elongational flow, our model predicts that VWF is 50% unfolded at approximately <jats:inline-formula><jats:alternatives><jats:tex-math>$$2000\,\text {s}^{-1}$$</jats:tex-math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mn>2000</mml:mn> <mml:mspace /> <mml:msup> <mml:mtext>s</mml:mtext> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> </mml:mrow> </mml:math></jats:alternatives></jats:inline-formula>, matching the established hypothesis that VWF unfolds at lower shear rates in elongational flow than in shear flow. We demonstrate the sensitivity of this elongational flow prediction to the value of maximum VWF length used in the model, which varies significantly across experimental studies, predicting that VWF can unfold between <jats:inline-formula><jats:alternatives><jats:tex-math>$$2000\text { and }3200\,\text {s}^{-1}$$</jats:tex-math><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mn>2000</mml:mn> <mml:mspace /> <mml:mtext>and</mml:mtext> <mml:mspace /> <mml:mn>3200</mml:mn> <mml:mspace /> <mml:msup> <mml:mtext>s</mml:mtext> <mml:mrow> <mml:mo>-</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> </mml:mrow> </mml:math></jats:alternatives></jats:inline-formula> depending on the selected value. Finally, we examine VWF dynamics in a range of idealised arterial stenoses, predicting the relative extension of VWF in elongational flow structures in the centre of the artery compared to high shear regions near the arterial walls.</jats:p>
Flow Dynamics in Stented Ureter
Urinary flow is governed by the principles of fluid mechanics. Urodynamic studies have revealed the fundamental kinematics and dynamics of urinary flow in various physiological and pathological conditions, which are cornerstones for future development of diagnostic knowledge and innovative devices. There are three primary approaches to study the fluid mechanical characteristics of urinary flow: reduced order, computational, and experimental methods. Reduced-order methods exploit the disparate length scales inherent in the system to reveal the key dominant physics. Computational models can simulate fully three-dimensional, time-dependent flows in physiologically-inspired anatomical domains. Finally, experimental models provide an excellent counterpart to reduced and computational models by providing physical tests under various physiological and pathological conditions. While the interdisciplinary approaches to date have provided a wealth of insight into the fluid mechanical properties of the stented ureter, the next challenge is to develop new theoretical, computational and experimental models to capture the complex interplay between the fluid dynamics in stented ureters and biofilm/encrustation growth. Such studies will (1) enable identification of clinically relevant scenarios to improve patients’ treatment, and (2) provide physical guidelines for next-generation stent design.