Developing a coordinate-based strategy to support cognitive targeted prostate biopsies and correlative spatial-histopathological outcome analysis

Lack of investment for magnetic resonance(MR)fusion systems is an obstacle to deliver targeted prostate biopsies within the prostate cancer diagnostic pathway.W...     

Dynamic porous organic polymers with tuneable crosslinking degree and porosity

Porous organic polymers (POPs) show enormous potential for applications in separation, organic electronics, and biomedicine due to the combination of high porosity, high stability, and ease of functionalisation. However, POPs are usually insoluble and amorphous materials making it very challenging to obtain structural information. Additionally, important parameters such as the exact molecular structure or the crosslinking degree are largely unknown, despite their importance for the final properties of the system. In this work, we introduced the reversible multi-fold nitroxide exchange reaction to the synthesis of POPs to tune and at the same time follow the crosslinking degree in porous polymer materials. We synthesised three different POPs based on the combination of linear, trigonal, and tetrahedral alkoxyamines with a tetrahedral nitroxide. We could show that modulating the equilibrium in the nitroxide exchange reaction, by adding or removing one nitroxide species, leads to changes in the crosslinking degree. Being able to modulate the crosslinking degree in POPs allowed us to investigate both the influence of the crosslinking degree and the structure of the molecular components on the porosity. The crosslinking degree of the frameworks was characterised using EPR spectroscopy and the porosity was determined using argon gas adsorption measurements. To guide the design of POPs for desired applications, our study reveals that multiple factors need to be considered such as the structure of the molecular building blocks, the synthetic conditions, and the crosslinking degree.

We synthesised three different POPs via a nitroxide exchange reaction and modulated their crosslinking degree. That allowed us to investigate the influence of the crosslinking degree and the structure of the molecular components on the porosity.

Various approaches to synthesise porous organic polymers (POPs)^1–3 and conjugated microporous polymers (CMPs)^4,5 have been developed to form extremely stable but at the same time highly porous solids based on simple organic building blocks.^6,7 The organic nature allows for functionalisation of the materials using organic chemistry, while the high porosity makes the active components accessible throughout the entire material.⁸ The combination of high porosity, high stability, and ease of functionalisation results in the enormous potential of POPs for applications in separation, organic electronics, and biomedicine.^2,9–14 However, unlike the related covalent organic frameworks (COFs),^15–20 metal–organic frameworks (MOFs)^21,22 or porous coordination polymers (PCPs),²³ the synthesis of POPs and CMPs is based on irreversible reactions, which leads to insoluble and amorphous materials and makes it very challenging to obtain structural information. Additionally, important parameters such as the exact molecular structure or the crosslinking degree are largely unknown, despite their unarguably large influence on the final properties of the system.^24,25To investigate the molecular structure of the organic linkers between the centres of two similar CMP materials, the group of Bunz and co-workers introduced molecular building blocks that were modified with digestible groups or cores, by substituting carbon with tin as the central atom.²⁴ This tin centre can be digested, resulting in molecular fragments of the frameworks, which were analysed using nuclear magnetic resonance (NMR) spectroscopy. The obtained fragments show a surprisingly varied chemical composition of these networks.²⁴ In a previous study, we could show that the introduction of digestible germanium nodes in one of the building blocks of POPs can also be used for partial disruption of the framework and therefore causing a decrease or allow tuning of the porosity.²⁵ In another approach, we introduced a poly(disulfide) hyper-crosslinked polymer, which can be surface modified using unreacted thiol functions on the surface of the material.²⁶ Digestion of the samples helped to quantify the functionalisation. Employing digestible crosslinker or nodes is an attractive approach to gain insight into the structure or functionalisation of the frameworks. However, it requires the destruction of the sample and does not allow to modulate or tune the crosslinking degree reversibly in one particular system.In order to tune and at the same time follow the crosslinking degree in porous polymer materials, we introduce the reversible multi-fold nitroxide exchange reaction to the synthesis of POPs. The nitroxide exchange reaction has been used in material science for self-assembly of polymer materials²⁷ or micron-sized crystals,²⁸ for surface functionalisation,²⁹ or introducing self-healing properties to materials.³⁰ In addition, the combination of light-sensitive alkoxyamines was employed in surface coating³¹ or the creation of systems out of their equilibrium.³² The radical nature of the involved nitroxide species allows to follow the progress of the reaction and to directly determine the crosslinking degree of the final material using fluorescence spectroscopy^33,34 and electron paramagnetic resonance (EPR) spectroscopy.^35,36 The dynamic nature of the nitroxide exchange reaction allowed us to tune the crosslinking degree of the materials by varying the ratio of the two nitroxide species involved in the reaction and thereby modulating the equilibrium conditions (see Fig. 1).Open in a separate windowFig. 1Dynamic equilibrium in the nitroxide exchange reaction using two different nitroxide species, TEMPO (red) and isoindoline (green). The free nitroxide radical species are electron paramagnetic resonance (EPR) active, while the bound species are EPR silent.Next to the crosslinking degree, also the structure, rigidity, and the intrinsic free volume of the molecular components of POPs or CMPs play an important role to obtain porosity in the final material.⁶ Cooper and co-workers showed the importance of monomer design for the pore size and surface area of CMPs by systematically varying the strut length in a series of molecular building blocks.³⁷In order to study the influence of both the molecular structure and the crosslinking degree on the porosity of the final material, we produced three different POPs based on the combination of linear, trigonal, and tetrahedral alkoxyamines with tetrahedral nitroxides. We characterised the frameworks using EPR spectroscopy and argon gas adsorption measurements to determine the crosslinking degree and porosity. Furthermore, we could show that modulating the equilibrium in the nitroxide exchange reaction, by adding or removing one nitroxide species, leads to changes in the crosslinking degree and investigated this influence on the porosity of the frameworks.     

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

Ischemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long‐term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow–derived mesenchymal stem/stromal cell (BM‐MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM‐MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM‐MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell‐based combination treatments.     

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.     

A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales,Australia

Four hundred and twenty‐one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross‐sectional study to assess sexual dysfunction and infertility post‐transplant. Survey instruments included the Sydney Post‐Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) – BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft‐versus‐Host Disease (cGVHD) Activity Assessment‐ Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post‐Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo‐HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre‐ and post‐transplant.     

Gut microbiome:a balancing act between degeneration and regeneration

In a symbiotic and mutualistic manner,the gut microbiota strongly influences many vital aspects of host physiology,biology,repair,and regeneration.The role of microbiota in many areas of regenerative medicine is just beginning to emerge,but it is under-recognized because of its complexity.As we remove the barriers that impede our understanding of this complex entity,we will uncover some of the most vital facets of our microbiome that make us who we are,its intrinsic connection with not only our wellbeing,but also with regeneration within.This will subsequently define its utility in regenerative medicine.