Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis.

INTRODUCTION: Recent advances in understanding the biology of ankylosing spondylitis (AS) using innovative genomic and proteomic approaches offer the opportunity to address current challenges in AS diagnosis and management. Altered expression of genes, microRNAs (miRNAs) or proteins may contribute to immune dysregulation and may play a significant role in the onset and persistence of inflammation in AS. The ability of exosomes to transport miRNAs across cells and alter the phenotype of recipient cells has implicated exosomes in perpetuating inflammation in AS. This study reports the first proteomic and miRNA profiling of plasma-derived exosomes in AS using comprehensive computational biology analysis. METHODS: Plasma samples from patients with AS and healthy controls (HC) were isolated via ultracentrifugation and subjected to extracellular vesicle flow cytometry analysis to characterise exosome surface markers by a multiplex immunocapture assay. Cytokine profiling of plasma-derived exosomes and cell culture supernatants was performed. Next-generation sequencing was used to identify miRNA populations in exosomes enriched from plasma fractions. CD4+ T cells were sorted, and the frequency and proliferation of CD4+ T-cell subsets were analysed after treatment with AS-exosomes using flow cytometry. RESULTS: The expression of exosome marker proteins CD63 and CD81 was elevated in the patients with AS compared with HC (q<0.05). Cytokine profiling in plasma-derived AS-exosomes demonstrated downregulation of interleukin (IL)-8 and IL-10 (q<0.05). AS-exosomes cocultured with HC CD4+ T cells induced significant upregulation of IFNα2 and IL-33 (q<0.05). Exosomes from patients with AS inhibited the proliferation of regulatory T cells (Treg), suggesting a mechanism for chronically activated T cells in this disease. Culture of CD4+ T cells from healthy individuals in the presence of AS-exosomes reduced the proliferation of FOXP3+ Treg cells and decreased the frequency of FOXP3+IRF4+ Treg cells. miRNA sequencing identified 24 differentially expressed miRNAs found in circulating exosomes of patients with AS compared with HC; 22 of which were upregulated and 2 were downregulated. CONCLUSIONS: Individuals with AS have different immunological and genetic profiles, as determined by evaluating the exosomes of these patients. The inhibitory effect of exosomes on Treg in AS suggests a mechanism contributing to chronically activated T cells in this disease.

Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester.

A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno-Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z-selective cross-metathesis to introduce the (Z)-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z-selective cross-metathesis protocol to construct (Z)-ß,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18 O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

An interprofessional approach to managing children with treatment-resistant enuresis: an educational review.

Enuresis (intermittent urinary incontinence during sleep in a child aged ≥ 5 years) is commonly seen in paediatric practice. Despite the availability of effective interventions, treatment resistance is encountered in up to 50% of children. In this educational review we attempt to provide insight into the causes of treatment resistance, and offer practical suggestions for addressing this condition using an interprofessional approach. We explore the pathophysiology of and standard treatments for enuresis and discuss why standard treatments may fail. An interprofessional approach to treatment resistance is proposed which utilises the expertise of professionals from different disciplines to address the problems and barriers to treatment. The two interprofessional approaches include a multidisciplinary approach that involves the patient being sent to experts in different disciplines at different times to address their treatment resistance utilising the skills of the respective experts, and an interdisciplinary approach that involves a patient being managed by members of interdisciplinary team who integrate their separate discipline perspectives into a single treatment plan. Although an interdisciplinary approach is ideal, interdisciplinary teams may not be available in all circumstances. Understanding the roles of other disciplines and engaging clinicians from other disciplines when appropriate can still be helpful when treatment resistance is encountered.

Health related quality of life assessment in acute coronary syndrome patients: the effectiveness of early phase I cardiac rehabilitation.

BACKGROUND: Acute Coronary Syndrome (ACS) is one of the most burdensome cardiovascular diseases in terms of the cost of interventions. The Cardiac Rehabilitation Programme (CRP) is well-established in improving clinical outcomes but the assessment of actual clinical improvement is challenging, especially when considering pharmaceutical care (PC) values in phase I CRP during admission and upon discharge from hospital and phase II outpatient interventions. This study explores the impact of pharmacists' interventions in the early stages of CRP on humanistic outcomes and follow-up at a referral hospital in Malaysia. METHODS: We recruited 112 patients who were newly diagnosed with ACS and treated at the referral hospital, Sarawak General Hospital, Malaysia. In the intervention group (modified CRP), all medication was reviewed by the clinical pharmacists, focusing on drug indication; understanding of secondary prevention therapy and adherence to treatment strategy. We compared the "pre-post" quality of life (QoL) of three groups (intervention, conventional and control) at baseline, 6 months and 12 months post-discharge with Malaysian norms. QoL data was obtained using a validated version of Short-Form 36 Questionnaire (SF-36). Analysis of variance (ANOVA) with repeated measure tests was used to compare the mean differences of scores over time. RESULTS: A pre-post quasi-experimental non-equivalent group comparison design was applied to 112 patients who were followed up for one year. At baseline, the physical and mental health summaries reported poor outcomes in all three groups. However, these improved gradually but significantly over time. After the 6-month follow-up, the physical component summary reported in the modified CRP (MCRP) participants was higher, with a mean difference of 8.02 (p = 0.015) but worse in the mental component summary, with a mean difference of -4.13. At the 12-month follow-up, the MCRP participants performed better in their physical component (PCS) than those in the CCRP and control groups, with a mean difference of 11.46 (p = 0.008), 10.96 (p = 0.002) and 6.41 (p = 0.006) respectively. Comparing the changes over time for minimal important differences (MICD), the MCRP group showed better social functioning than the CCRP and control groups with mean differences of 20.53 (p = 0.03), 14.47 and 8.8, respectively. In role emotional subscales all three groups showed significant improvement in MCID with mean differences of 30.96 (p = 0.048), 31.58 (p = 0.022) and 37.04 (p < 0.001) respectively. CONCLUSION: Our results showed that pharmaceutical care intervention significantly improved HRQoL. The study also highlights the importance of early rehabilitation in the hospital setting. The MCRP group consistently showed better QoL, was more highly motivated and benefitted most from the CRP. TRIAL REGISTRATION: Medical Research and Ethics Committee (MREC) Ministry of Health Malaysia, November 2007, NMRR-08-246-1401.

A smartphone-based approach for comprehensive soil microbiome profiling.

The soil microbiome is crucial for nutrient cycling, health, and plant growth. This study presents a smartphone-based approach as a low-cost and portable alternative to traditional methods for classifying bacterial species and characterizing microbial communities in soil samples. By harnessing bacterial autofluorescence detection and machine learning algorithms, the platform achieved an average accuracy of 88% in distinguishing common soil-related bacterial species despite the lack of biomarkers, nucleic acid amplification, or gene sequencing. Furthermore, it successfully identified dominant species within various bacterial mixtures with an accuracy of 76% and three-level soil health identification at an accuracy of 80%-82%, providing insights into microbial community dynamics. The influence of other soil conditions (pH and moisture) was relatively minor, showcasing the platform's robustness. Various field soil samples were also tested with this platform at 80% accuracy compared with the laboratory analyses, demonstrating the practicality and usability of this approach for on-site soil analysis. This study highlights the potential of the smartphone-based system as a valuable tool for soil assessment, microbial monitoring, and environmental management.

DCAF16-Based Covalent Handle for the Rational Design of Monovalent Degraders.

Targeted protein degradation with monovalent molecular glue degraders is a powerful therapeutic modality for eliminating disease causing proteins. However, rational design of molecular glue degraders remains challenging. In this study, we sought to identify a transplantable and linker-less covalent handle that could be appended onto the exit vector of various protein-targeting ligands to induce the degradation of their respective targets. Using the BET family inhibitor JQ1 as a testbed, we synthesized and screened a series of covalent JQ1 analogs and identified a vinylsulfonyl piperazine handle that led to the potent and selective degradation of BRD4 in cells. Through chemoproteomic profiling, we identified DCAF16 as the E3 ligase responsible for BRD4 degradation-an E3 ligase substrate receptor that has been previously covalently targeted for molecular glue-based degradation of BRD4. Interestingly, we demonstrated that this covalent handle can be transplanted across a diverse array of protein-targeting ligands spanning many different protein classes to induce the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL. Our study reveals a DCAF16-based covalent degradative and linker-less chemical handle that can be attached to protein-targeting ligands to induce the degradation of several different classes of protein targets.

Enhanced Type 1 Interferon Signature in Axial Spondyloarthritis Patients Unresponsive to Secukinumab Treatment.

OBJECTIVE: Axial spondyloarthritis (axSpA) is an inflammatory disease in which overactive IL-17A-producing cells are implicated in a central role. Therapeutically, biologics that target IL-17A, such as secukinumab, have demonstrated improved clinical outcomes. Despite this translational success, there is a gap in understanding why some axSpA patients do not respond to IL-17A blocking therapy. Our study aims to discriminate immune profiles between secukinumab responders (SEC-R) and nonresponders (SEC-NR). METHODS: Peripheral blood mononuclear cells were collected from 30 axSpA patients before and 24-weeks after secukinumab treatment. Frequency of CD4+ subsets were compared between SEC-R and SEC-NR using flow cytometry. Mature CD45RO+CD45RA-CD4+ T cells were FACS sorted, and RNA was measured using NanoString analysis. RESULTS: SEC-NR had an increased frequency of IL-17A-producing RORγt+CD4+ T cells compared to HCs at pre-secukinumab (p<0.01). SEC-NR had a significant increase of CXCR3+ CD4+ T cells pre-secukinumab compared to SEC-R (p<0.01). Differentially expressed gene analysis revealed upregulation of type 1 interferon-regulated genes in SEC-NR patients compared to SEC-R post-biologic. SEC-R patients had an upregulated cytotoxic CD4+ T cell gene signature pre-secukinumab compared to SEC-NR patients. CONCLUSIONS: The increased frequency of IL-17A-producing cells in SEC-NR patients suggests a larger inflammatory burden than SEC-R patients. With treatment, SEC-NR patients have a more pronounced type 1 IFN signature than SEC-R patients, suggesting a mechanism contributing to this larger inflammatory burden. The results point toward more immune heterogeneity in axSpA than has been recognized and highlights the need for precision therapeutics in this disease.

Gaps in cancer care in a multi-ethnic population in Sarawak, Borneo: A central referral centre study.

BACKGROUND: The state of Sarawak on the island of Borneo in East Malaysia, in working towards developing and strengthening cancer services through a holistic patient-centred approach, must focus on the comprehensive needs of cancer patients by taking into account the psycho-social, cultural and spiritual aspects of Sarawak's multi-ethnic, multi-cultural population. METHODS: A 42-item survey questionnaire was developed and validated with a total of 443 patients. The perceived importance of information provided and level of patient satisfaction were assessed with a 5-point Likert scale in 10 domains (Diagnosis, Surgery, Radiotherapy, Systemic therapy, Clinical trials, Pain management, Treatment monitoring, Psychosocial support, Sexual care and fertility issues, and Financial support). A Spearman's rank correlation test was applied to determine the correlation between response in both item and domain categories for perceived importance and satisfaction. RESULTS: Overall, patients were more satisfied with information related to cancer diagnosis, treatment and surgery but less satisfied with information pertaining to sexual aspects of care and family planning, psycho-social support and financial support. The majority of patients were satisfied with the level of treatment-related information received but preferred the information to be delivered in more easily comprehendible formats. Sexual aspects of care and family planning, psychosocial support and treatment monitoring post-discharge were perceived as important but seldom addressed by health care professionals due to lack of professional counsellors, social workers and clinical nurse specialists. Many patients face financial toxicity following a cancer diagnosis, particularly when diagnosed with advanced cancer requiring complex multi-modality treatment. CONCLUSION: Cancer patients in Sarawak have various unmet information needs. Written information and educational videos in local indigenous languages may be more suitable for Sarawak's multi-ethnic population. Sexual aspects of care and family planning are challenging but essential topics to discuss, in particular due to the high prevalence of breast and cervical cancer amongst young women of reproductive age in Sarawak. Financial assessment and information on support services offered by government and non-government organisations should be provided to eligible patients. A holistic needs assessment of each patient at time of diagnosis and support through their cancer journey requires a multi-disciplinary team of medical, nursing and allied health professionals including clinical nurse specialists, pharmacists, counsellors, physiotherapists, occupational therapists, speech and language therapists, dieticians and social workers.

A portfolio analysis of autism research funding in Aotearoa New Zealand 2007-2021.

LAY ABSTRACT: We aimed to document the areas of autism research that have previously been funded in Aotearoa New Zealand. We searched for research grants awarded to autism research in Aotearoa New Zealand between 2007 and 2021. We compared the funding distribution in Aotearoa New Zealand to other countries. We asked people from the autistic community and broader autism community whether they were satisfied with this funding pattern, and whether it aligned with what is important to them and to autistic people. We found that the majority of funding for autism research was awarded to biology research (67%). Members of the autistic and autism communities were dissatisfied with the funding distribution, and expressed a lack of alignment with what is important to them. People from the community indicated that the funding distribution did not address the priorities of autistic people, and that it indicated a lack of engagement with autistic people. Autism research funding needs to reflect the priorities of the autistic and autism communities. Autistic people need to be included in autism research and related funding decisions.

Acceptability and Usability of a Wearable Device for Sleep Health Among English- and Spanish-Speaking Patients in a Safety Net Clinic: Qualitative Analysis.

BACKGROUND: Sleep disorders are common and disproportionately affect marginalized populations. Technology, such as wearable devices, holds the potential to improve sleep quality and reduce sleep disparities, but most devices have not been designed or tested with racially, ethnically, and socioeconomically diverse patients. Inclusion and engagement of diverse patients throughout digital health development and implementation are critical to achieving health equity. OBJECTIVE: This study aims to evaluate the usability and acceptability of a wearable sleep monitoring device-SomnoRing-and its accompanying mobile app among patients treated in a safety net clinic. METHODS: The study team recruited English- and Spanish-speaking patients from a mid-sized pulmonary and sleep medicine practice serving publicly insured patients. Eligibility criteria included initial evaluation of obstructed sleep apnea, which is most appropriate for limited cardiopulmonary testing. Patients with primary insomnia or other suspected sleep disorders were not included. Patients tested the SomnoRing over a 7-night period and participated in a 1-hour semistructured web-based qualitative interview covering perceptions of the device, motivators and barriers to use, and general experiences with digital health tools. The study team used inductive or deductive processes to code interview transcripts, guided by the Technology Acceptance Model. RESULTS: A total of 21 individuals participated in the study. All participants owned a smartphone, almost all (19/21) felt comfortable using their phone, and few already owned a wearable (6/21). Almost all participants wore the SomnoRing for 7 nights and found it comfortable. The following four themes emerged from qualitative data: (1) the SomnoRing was easy to use compared to other wearable devices or traditional home sleep testing alternatives, such as the standard polysomnogram technology for sleep studies; (2) the patient's context and environment, such as family and peer influence, housing status, access to insurance, and device cost affected the overall acceptance of the SomnoRing; (3) clinical champions motivated use in supporting effective onboarding, interpretation of data, and, ongoing technical support; and (4) participants desired more assistance and information to best interpret their own sleep data summarized in the companion app. CONCLUSIONS: Racially, ethnically, and socioeconomically diverse patients with sleep disorders perceived a wearable as useful and acceptable for sleep health. Participants also uncovered external barriers related to the perceived usefulness of the technology, such as housing status, insurance coverage, and clinical support. Future studies should further examine how to best address these barriers so that wearables, such as the SomnoRing, can be successfully implemented in the safety net health setting.

Ensuring Global Access to Cancer Medicines: A Generational Call to Action.

SUMMARY: Essential cancer treatments are not accessible, affordable, or available to patients who need them in many parts of the world. A new Access to Oncology Medicines (ATOM) Coalition, using public-private partnerships, aims to bring essential cancer medicines and diagnostics to patients in low- and lower middle-income countries.

First-in-human clinical trial of allogeneic, platelet-derived extracellular vesicles as a potential therapeutic for delayed wound healing.

The release of growth factors, cytokines and extracellular matrix modifiers by activated platelets is an important step in the process of healthy wound healing. Extracellular vesicles (EVs) released by activated platelets carry this bioactive cargo in an enriched form, and may therefore represent a potential therapeutic for the treatment of delayed wound healing, such as chronic wounds. While EVs show great promise in regenerative medicine, their production at clinical scale remains a critical challenge and their tolerability in humans is still to be fully established. In this work, we demonstrate that Ligand-based Exosome Affinity Purification (LEAP) chromatography can successfully isolate platelet EVs (pEVs) of clinical grade from activated platelets, which retain the regenerative properties of the parent cell. LEAP-isolated pEVs display the expected biophysical features of EV populations and transport essential proteins in wound healing processes, including insulin growth factor (IGF) and transforming growth factor beta (TGF-ß). In vitro studies show that pEVs induce proliferation and migration of dermal fibroblasts and increase dermal endothelial cells' angiogenic potential, demonstrating their wound healing potential. pEV treatment activates the ERK and Akt signalling pathways within recipient cells. In a first-in-human, double-blind, placebo-controlled, phase I clinical trial of healthy volunteer adults, designed primarily to assess safety in the context of wound healing, we demonstrate that injections of LEAP-purified pEVs in formulation buffer are safe and well tolerated (Plexoval II study, ACTRN12620000944932). As a secondary objective, biological activity in the context of wound healing rate was assessed. In this cohort of healthy participants, in which the wound bed would not be expected to be deficient in the bioactive cargo that pEVs carry, all wounds healed rapidly and completely and no difference in time to wound closure of the treated and untreated wounds was observed at the single dose tested. The outcomes of this study evidence that pEVs manufactured through the LEAP process can be injected safely in humans as a potential wound healing treatment, and warrant further study in clinical trials designed expressly to assess therapeutic efficacy in patients with delayed or disrupted wound healing.

The impact of mobility scooter on occupational participation among older adults in Singapore: an exploratory study.

PURPOSE: With an ageing population, the use of mobility scooters by community-dwelling older adults with mobility limitations has been increasingly prevalent in Singapore. Their experiences in using mobility scooters remain unclear. This study aimed to explore the impact of mobility scooters on occupational performance and engagement among elderly Singaporeans. MATERIALS AND METHODS: Mobility scooter users were recruited via purposive and snowballing sampling. Semi-structured interviews were conducted in English or Mandarin via phone call or face-to-face and audio-recorded with permission. Interviews were transcribed verbatim in their original language and translated to English (when applicable) for thematic analysis. RESULTS: Twelve eligible participants (mean age: 75 years) completed the interviews. They were predominantly female Chinese with 7 receiving training from occupational therapists (OT). Four main themes emerged from the interviews describing their experiences of using mobility scooters: factors of decision-making in getting a mobility scooter, enhanced occupational participation with the use of the mobility scooter, enablers for community participation and barriers to community participation. Despite having barriers, older adults with mobility limitations generally still had positive experiences to continue using mobility scooters to perform occupations in the community. CONCLUSIONS: This study highlights the benefits of mobility scooters in supporting users' occupational performance and engagement in the community. Continual efforts are required from all stakeholders to provide an accessible environment and improve societal attitudes to further support the mobility scooter users.IMPLICATIONS FOR REHABILITATIONMobility scooter users can be deterred from performing their preferred occupations if they had a prior negative encounter and they mainly rely on self-developed coping strategies to overcome possible barriers in the community.Occupational therapists should identify and address the potential barriers when prescribing mobility scooters to older adult users.Occupational therapists should work collaboratively with other key stakeholders, such as external vendors and government agencies, to co-create a universal guideline to support and safeguard mobility scooter users.

Tankyrase represses autoinflammation through the attenuation of TLR2 signaling.

Dysregulation of Toll-like receptor (TLR) signaling contributes to the pathogenesis of autoimmune diseases. Here, we provide genetic evidence that tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, negatively regulates TLR2 signaling. We show that mice lacking tankyrase in myeloid cells developed severe systemic inflammation with high serum inflammatory cytokine levels. We provide mechanistic evidence that tankyrase deficiency resulted in tyrosine phosphorylation and activation of TLR2 and show that phosphorylation of tyrosine 647 within the TIR domain by SRC and SYK kinases was critical for TLR2 stabilization and signaling. Last, we show that the elevated cytokine production and inflammation observed in mice lacking tankyrase in myeloid cells were dependent on the adaptor protein 3BP2, which is required for SRC and SYK activation. These data demonstrate that tankyrase provides a checkpoint on the TLR-mediated innate immune response.

The gut-joint axis in spondyloarthritis: immunological, microbial, and clinical insights.

The strong genetic and clinical overlaps between spondyloarthritis (SpA) and inflammatory bowel disease (IBD) have placed much needed focus on the gut-joint axis of inflammation in SpA, leading to three key hypotheses that attempt to unravel this complex relationship. The arthritogenic peptide hypothesis and the aberrant cellular trafficking hypothesis have been put forth to rationalize the manner by which the innate and adaptive immune systems cooperate and converge during SpA pathogenesis. The bacterial dysbiosis hypothesis discusses how changes in the microbiome lead to architectural and immunological consequences in SpA. These theories are not mutually exclusive, but can provide an explanation as to why subclinical gut inflammation may sometimes precede joint inflammation in SpA patients, thereby implying a causal relationship. Such investigations will be important in informing therapeutic decisions which may be common to both SpA and IBD. However, these hypotheses can also offer insights for a coincident inflammatory relationship between the gut and the joint, particularly when assessing the immunological players involved. Insights from understanding how these systems might affect the gut and joint differently will be equally imperative to address where the therapeutic differences lie between the two diseases. Collectively, this knowledge has practical implications in predicting the likelihood of IBD development in SpA or presence of coincident SpA-IBD, uncovering novel therapeutic targets, and redesigning currently approved treatments. It is evident that a multidisciplinary approach between the rheumatology and gastroenterology fields cannot be ignored, when it comes to the care of SpA patients at risk of IBD or vice versa.

Lactosome-Conjugated siRNA Nanoparticles for Photo-Enhanced Gene Silencing in Cancer Cells.

The A3B-type Lactosome comprised of poly(sarcosine)3-block-poly(l-lactic acid), a biocompatible and biodegradable polymeric nanomicelle, was reported to accumulate in tumors in vivo via the enhanced permeability and retention (EPR) effect. Recently, the cellular uptake of Lactosome particles was enhanced through the incorporation of a cell-penetrating peptide (CPP), L7EB1. However, the ability of Lactosome as a drug delivery carrier has not been established. Herein, we have developed a method to conjugate the A3B-type Lactosome with ATP-binding cassette transporter G2 (ABCG2) siRNA for inducing in vitro apoptosis in the cancer cell lines PANC-1 and NCI-H226. The L7EB1 peptide facilitates the cellular uptake efficiency of Lactosome but does not deliver siRNA into cytosol. To establish the photoinduced cytosolic dispersion of siRNA, a photosensitizer loaded L7EB1-Lactosome was prepared, and the photosensitizer 5,10,15,20-tetra-kis(pentafluorophenyl)porphyrin (TPFPP) showed superiority in photoinduced cytosolic dispersion. We exploited the combined effects of enhanced cellular uptake by L7EB1 and photoinduced endosomal escape by TPFPP to efficiently deliver ABCG2 siRNA into the cytosol for gene silencing. Moreover, the silencing of ABCG2, a protoporphyrin IX (PpIX) transporter, also mediated photoinduced cell death via 5-aminolevulinic acid (ALA)-mediated PpIX accumulated photodynamic therapy (PDT). The synergistic capability of the L7EB1/TPFPP/siRNA-Lactosome complex enabled both gene silencing and PDT.

A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): "Lactosome" Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy.

"Theranostics," a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, "Lactosome" nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the "89Zr-labeled CPP and TPP-loaded Lactosome particles" and future directions based on important milestones and recent developments in this platform.

Macrophage migration inhibitory factor drives pathology in a mouse model of spondyloarthritis and is associated with human disease.

Spondyloarthritis (SpA), a type 3 immunity-mediated inflammatory arthritis, is a systemic rheumatic disease that primarily affects the joints, spine, gut, skin, and eyes. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, yet MIF's pathological role in SpA is unknown. Here, we observed that the expression of MIF and its receptor CD74 is increased in blood and tissues of curdlan (ß-glucan)­treated SKG mice, a mouse model of SpA. We found that neutrophils substantially expanded and produced MIF in curdlan-treated SKG mice and that human neutrophils from SpA patients secreted higher concentrations of MIF compared to healthy individuals. Although genetic deletion of Mif (Mif−/−) substantially suppressed the severity of SpA features, adoptive transfer of inflammatory neutrophils induced SpA pathology in curdlan-treated Mif−/− SKG mice; in contrast, blocking the function of neutrophils with anti­Gr-1 antibody suppressed the curdlan-induced SpA-like phenotype. We also determined that systemic MIF overexpression was sufficient to induce SpA-like clinical features in SKG mice with enhanced type 3 immunity, whereas SKG mice treated with a MIF antagonist prevented or attenuated curdlan-induced SpA manifestations. Mechanistically, we identified that MIF intensifies type 3 immunity by boosting human and mouse T regulatory cell (Treg) acquisition of a TH17 cell­like phenotype, including the up-regulation of interleukin-17 (IL-17) and IL-22 in vitro. Tregs in blood and synovial fluids from SpA patients have a pathologic TH17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.

Altered Cytotoxicity Profile of CD8+ T Cells in Ankylosing Spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA-B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients. METHODS: Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence-activated cell sorting (FACS). RESULTS: GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme-positive and perforin 1-positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients. CONCLUSION: Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.