Clinical Outcomes and Quality of Life of Patients Receiving Multi-Solid-Organ Transplants in Childhood Are Excellent: Results From a 20-Year Cohort Study.

Advances in medicine allow children with previously fatal conditions to survive longer and present as transplant candidates; some requiring multiple solid-organ transplants (MSOT). There is limited data on clinical outcomes and no data on quality of life (QoL). In this mixed methods cohort study clinical outcomes from the NHSBT registry were analysed for all patients who received a kidney and one other solid-organ transplant as a child between 2000 and 2021 in the UK.

Efficient, multi-hundred-gram scale access to E3 ubiquitin ligase ligands for degrader development.

Small molecule heterobifunctional degraders (commonly also known as PROTACs) offer tremendous potential to deliver new therapeutics in areas of unmet medical need. To deliver on this promise, a new discipline directed at degrader design and optimization has emerged within medicinal chemistry to address a central challenge, namely how to optimize relatively large, heterobifunctional molecules for activity, whilst maintaining drug-like properties. This process involves simultaneous optimization of the three principle degrader components: E3 ubiquitin ligase ligand, linker, and protein of interest (POI) ligand.

Chirality: a key parameter in chemical probes.

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer.

Exploring Staff Attitudes Towards Unspecified Kidney Donors in the United Kingdom: Results From the BOUnD Study.

Unspecified kidney donation (UKD) has made substantial contributions to the UK living donor programme. Nevertheless, some transplant professionals are uncomfortable with these individuals undergoing surgery. This study aimed to qualitatively explore the attitudes of UK healthcare professionals towards UKD.

Donating a Kidney to a Stranger: Are Healthcare Professionals Facilitating the Journey? Results From the BOUnD Study.

Unspecified kidney donors (UKDs) are approached cautiously by some transplant professionals. The aim of this study was to interrogate the views of UK transplant professionals towards UKDs and identify potential barriers. A purposely designed questionnaire was validated, piloted and distributed amongst transplant professionals at each of the 23 UK transplant centres.

Psychosocial and Clinical Associations of Fatigue Severity and Fatigue-Related Impairment in Kidney Transplant Recipients.

Debilitating fatigue is common in people living with kidney disease and often persists after a kidney transplant. Current understanding of fatigue is centered around pathophysiological processes. Little is known about the role of cognitive and behavioral factors.

Developing, Choosing, and Using the Chemical Toolbox for Infectious Diseases Research.

Scientific progress is built on "what went before". As research in a field or discipline progresses, laying strong and scientifically correct foundations for each incremental discovery ultimately accelerates progress. The importance of "research tools" (e.

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease.

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (M, 3CL) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. M is therefore an attractive target for the design of inhibitors that block viral replication.

Challenges and Opportunities in the Supply of Living Kidney Donation in the UK National Health Service: An Economic Perspective.

End-stage kidney disease is a significant burden on the healthcare systems of many countries, and this is likely to continue because of an increasingly aging and comorbid population. Multiple studies have demonstrated a significant clinical benefit in transplantation when compared with dialysis, however, there continues to be a shortage of donor kidneys available. This article provides an economic perspective on issues pertinent to living kidney donation and transplantation.

Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL.

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC = 0.65 μM) and BRD4 (IC = 1.5 μM) bromodomains, and a useful chemical probe for epigenetic research.

Donor Autonomy and Self-Sacrifice in Living Organ Donation: An Ethical Legal and Psychological Aspects of Transplantation (ELPAT) View.

Clinical teams understandably wish to minimise risks to living kidney donors undergoing surgery, but are often faced with uncertainty about the extent of risk, or donors who wish to proceed despite those risks. Here we explore how these difficult decisions may be approached and consider the conflicts between autonomy and paternalism, the place of self-sacrifice and consideration of risks and benefits. Donor autonomy should be considered as in the context of the depth and strength of feeling, understanding risk and competing influences.

α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways.

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues.

Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis.

Building a bridge between patients and transplant healthcare professionals - a descriptive study.

This article describes a pathway for collaboration between transplant healthcare professionals and organ recipients. Under the umbrella of the European Society for Organ Transplantation (ESOT) a joint initiative started from three Sections and Committees of ESOT: EDTCO (European Donation and Transplant Coordination Organisation), ETHAP (European Transplant Allied Healthcare Professionals) and ELPAT (Ethical, Legal and Psycho-social Aspects of Transplantation). The formal 'kick-off' of the Advisory Board Meeting of the European Transplant Patient Organisation (ETPO) was during the ESOT congress in 2019.

Reviewing the toolbox for degrader development in oncology.

The field of targeted protein degradation encompasses a growing number of modalities that achieve potent and selective knockdown of target proteins at the post-translational level. Among the most clinically advanced are bifunctional small-molecule degraders, also referred to as PROteolysis Targeting Chimeras, Degronimids, SNIPERs, or uSMITEs. Although applicable to many disease indications, oncology stands to be the first to benefit from this promising therapeutic approach, with the first investigational new drugs (INDs) filed in 2019 and a proliferation of research specifically focused on harnessing degraders for cancer treatment.

Experiences of completed and withdrawn unspecified kidney donor candidates in the United Kingdom: An inductive thematic analysis from the BOUnD study.

Objectives This study sheds light on some controversial aspects of unspecified kidney donation (UKD) as well as the ways in which potential donors are screened and prepared for the donation experience and its aftermath. The aim of this study was to qualitatively investigate the experiences of individuals involved in the United Kingdom (UK) UKD scheme, including those who complete the donation, are eventually medically withdrawn, or self-withdraw. Better insight into the different experiences of these groups will provide useful guidance to clinical teams on how to better address the differing psychological needs of completed donors as well as those who do not proceed to donation.

Solution Structure and Conformational Dynamics of a Doublet Acyl Carrier Protein from Prodigiosin Biosynthesis.

The acyl carrier protein (ACP) is an indispensable component of both fatty acid and polyketide synthases and is primarily responsible for delivering acyl intermediates to enzymatic partners. At present, increasing numbers of multidomain ACPs have been discovered with roles in molecular recognition of trans-acting enzymatic partners as well as increasing metabolic flux. Further structural information is required to provide insight into their function, yet to date, the only high-resolution structure of this class to be determined is that of the doublet ACP (two continuous ACP domains) from mupirocin synthase.

Donating a Kidney to a Stranger: A Review of the Benefits and Controversies of Unspecified Kidney Donation.

Of Background Data: Unspecified kidney donation (UKD) describes living donation of a kidney to a stranger. The practice is playing an increasingly important role within the transplant programme in the United Kingdom, where these donors are commonly used to trigger a chain of transplants; thereby amplifying the benefit derived from their donation. The initial reluctance to accept UKD was in part due to uncertainty about donor motivations and whether the practice was morally and ethically acceptable.

Developing degraders: principles and perspectives on design and chemical space.

Degraders ( PROTACs, SNIPERs, degronimers ) are a new modality offering increasing potential both as tools for basic research and therapeutic development. They occupy chemical space that lies outside the classical Lipinski 'Rule of 5', which poses fresh challenges for achieving cell permeability and oral bioavailability. This study presents a comprehensive database of degrader structures from the peer reviewed literature, including both optimized degraders and first generation compounds, in order to provide a thorough assessment of the chemical space associated with this modality and identify common trends used during the 'hit to lead' process.

The Effect of Pre-Analytical Conditions on Blood Metabolomics in Epidemiological Studies.

Serum and plasma are commonly used in metabolomic-epidemiology studies. Their metabolome is susceptible to differences in pre-analytical conditions and the impact of this is unclear. Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform ( = 151 traits).

Good long-term patency: 10-year follow-up using the mid-thigh adductor loop arteriovenous graft.

Introduction: Definitive access in patients requiring renal replacement therapy is an ever-increasing challenge. For those where autogenous venous access is no longer a viable option, arteriovenous grafts can be considered. This article describes long-term follow-up, complications and patency rates of the mid-thigh 'adductor loop' arteriovenous graft.

Donor and Recipient Perspectives on Anonymity in Kidney Donation From Live Donors: A Multicenter Survey Study.

Background: Maintaining anonymity is a requirement in the Netherlands and Sweden for kidney donation from live donors in the context of nondirected (or unspecified) and paired exchange (or specified indirect) donation. Despite this policy, some donors and recipients express the desire to know one another. Little empirical evidence informs the debate on anonymity.

Understanding barriers and outcomes of unspecified (non-directed altruistic) kidney donation from both professional's and patient's perspectives: research protocol for a national multicentre mixed-methods prospective cohort study.

Introduction: Living donation accounts for over one-third of all kidney transplants taking place in the UK. The concept of anonymously donating a kidney to a stranger (non-directed altruistic or unspecified kidney donation (UKD)) remains uncomfortable for some clinicians, principally due to concerns about the motivations and long-term physical and psychological outcomes in this donor group.

Aims: The research programme aims to provide a comprehensive assessment of the unspecified donor programme in the UK.

The ELPAT living organ donor Psychosocial Assessment Tool (EPAT): from 'what' to 'how' of psychosocial screening - a pilot study.

Thorough psychosocial screening of donor candidates is required in order to minimize potential negative consequences and to strive for optimal safety within living donation programmes. We aimed to develop an evidence-based tool to standardize the psychosocial screening process. Key concepts of psychosocial screening were used to structure our tool: motivation and decision-making, personal resources, psychopathology, social resources, ethical and legal factors and information and risk processing.