Current Disease Models Research Articles

Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments.

Aging is one of the most significant risk factors for breast cancer. With the growing interests in the alterations of the aging breast tissue microenvironment, it has been identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes. In this study, we utilized aged animal-generated materials to create and validate a novel age-mimetic breast cancer model that generates an aging microenvironment for cells and alters cells towards a phenotype found in the aged environment. Furthermore, we utilized the age-mimetic models for 3D breast cancer invasion assessment and high-throughput screening of over 700 drugs in the FDA-approved drug library. We identified 36 potential effective drug targets and 34 potential drug targets with different drug responses in different age groups, demonstrating the potential of this age-mimetic breast cancer model for further in-depth breast cancer studies and drug development.

8468 Development And Characterisation Of Three-Dimensional Cell Culture Models Of Adrenocortical Carcinoma

Abstract Disclosure: S. Feely: None. N. Mullen: None. P. Donlon: None. C. Hantel: None. M.C. dennedy: None. Adrenocortical carcinoma (ACC) is a rare malignancy carrying a poor prognosis and limited treatment options. Surgical resection is the only option for cure; but unsuitable for advanced disease. Mitotane is the approved medical therapy, but associated with treatment resistance and adverse effects. Newer therapies, such as immune checkpoint inhibitors, have limited success. Development of improved therapies is limited by current pre-clinical disease models. No available model reflects the tumour micro-environment. Three-dimensional (3D) cell culture models are increasingly used in cancer research (6), with a paucity of developed models in ACC. In the current study, we developed novel 3D models of ACC using a type-1 collagen matrix. We then characterised these as representative ACC disease models . 3D cell culture models of ACC were optimised by embedding ACC cell lines, MUC-1, HAC15 and H295R within a type-1 Collagen matrix at differing cell numbers. Expression of type-1 collagen in ACC primary tumours was determined using immunohistochemistry (n=4). Cell viability for each model was assessed by evaluating sytox blue staining by Flow Cytometry. Metabolic activity of ACC cells within the matrix was determined using AlamarBlue staining. Prolferative activity was assessed using Ki67. Steroidogenesis was evaluated by measuring cortisol, aldosterone and androstenedione using LC-MS/MS.. Expression of CYP11B1, CYP11B2 CYP17, and StAR was measured using RT-qPCR. Type 1 collagen is strongly expressed in ACC tumour microenvironment. MUC-1, H295R and HAC15 cells were successfully cultured in a type 1 collagen matrix. MUC-1 cells cultured in the collagen matrix remain viable throughout the period of experimentation with optimum viability between 14 and 21 days. H295R cells also remain viable with optimum viability at an earlier stage of 7-14 days. HAC15 cells demonstrate high resilience in 3D cell culture with maximum viability throughout the entire period of experimentation up to 21 days. All three models increase their metabolic and proliferative activity over time. All three steroids are expressed by all three models with an increase in aldosterone secretion observed in 3D HAC15 and H295R models compared to monolayer (p>0.001) at days 7 and 14. All models express key steroidogenic enzymes. 3D ACC cell culture models were developed successfully using collagen type 1 abundant in ACC. Typical characteristics of the ACC tumour environment included (i) the presence of live and necrotic cells (ii) high metabolic activity and proliferation, reflective of cell turnover.. Capacity of cells to spread and proliferate within the 3D cell culture models was limited by available collagen substrate. Steroidogenic capacity was demonstrated in 3D cell culture. This model therefore retained key characteristics of ACC and shows promise as an animal-sparing, pre-clinical model. Presentation: 6/1/2024

Microdissected tumor cuboids: a microscale cancer model for large-scale testing that retains a complex tumor microenvironment.

Current cancer disease models fail to faithfully recapitulate key features of the human tumor microenvironment (TME), such as immune and vascular cells, while simultaneously enabling high-throughput drug tests. We have recently developed a precision slicing method that optimizes the yield of large numbers of cuboidal microtissues ("cuboids", ∼(400 µm) 3 ) from a single tumor biopsy. Here we demonstrate that cuboids from syngeneic mouse tumor models and human tumors retain a complex TME, making them amenable for drug and immunotherapy evaluation. We characterize relevant TME parameters, such as cellular architecture, cytokine secretion, proteomics profiles, and response to drug panels in multi-well arrays. Despite the cutting procedure and the time spent in culture (up to 7 days), the cuboids display strong cytokine and drug responses, including to immunotherapy. Overall, our results suggest that cuboids could provide invaluable therapeutic information for personalized oncology applications, and could help the development of TME-dependent therapeutics and cancer disease models, including for clinical trials.

Vascularization of kidney organoids: different strategies and perspectives

Kidney diseases such as glomerulopathy and nephron dysfunction are estimated to grow to more than 900 million cases by 2030, in 45% of which kidney transplantation will be required, representing a major challenge for biomedicine. A wealth of progress has been made to model human diseases using induced pluripotent stem cells (iPSCs) in vitro differentiated to a variety of organoids, including kidney organoids, and in developing various microfluidics-based organ-on-a-chip (OoC) systems based on them. With the combination of targeted gene editing capacities, relevant polymorphic genetic variants can be established in such organoid models to advance evidence-based medicine. However, the major drawback of the current organoid disease models is the lack of functional endothelial vasculature, which especially concerns the kidney, the function of which is strongly associated with blood flow. The design of novel medical devices using tissue engineering approaches such as kidney organoids is also strongly dependent on the understanding of the fundamental principles of nephrogenesis and the vascularization of organs and tissues. Developmental vascularization of the kidney has been an area of intense research for decades. However, there is still no consensus among researchers on how exactly the vascularization of the kidney occurs in normal and pathological conditions. This lack of consensus is partly due to the lack of an appropriate model system to study renal vascularization during nephrogenesis. In this review, we will describe recent progress in the areas of kidney vasculature development, kidney organoids in general and assembled on microfluidic devices in particular. We will focus on the in vitro vasculature of kidney organoids in microfluidic OoC model systems to study kidney diseases and on the perspectives of tissue engineering for the modeling of kidney diseases and the design of bioartificial medical devices. We also aim to summarize the information related to the key mechanisms of intercellular communication during nephrogenesis and the formation of the renal vasculature in an OoC setup.

The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair.

The transient receptor potential vanilloid 4 (TRPV4) specifically functions as a mechanosensitive ion channel and is responsible for conveying changes in physical stimuli such as mechanical stress, osmotic pressure, and temperature. TRPV4 enables the entry of cation ions, particularly calcium ions, into the cell. Activation of TRPV4 channels initiates calcium oscillations, which trigger intracellular signaling pathways involved in a plethora of cellular processes, including tissue repair. Widely expressed throughout the body, TRPV4 can be activated by a wide array of physicochemical stimuli, thus contributing to sensory and physiological functions in multiple organs. This review focuses on how TRPV4 senses environmental cues and thereby initiates and maintains calcium oscillations, critical for responses to organ injury, tissue repair, and fibrosis. We provide a summary of TRPV4-induced calcium oscillations in distinct organ systems, along with the upstream and downstream signaling pathways involved. In addition, we delineate current animal and disease models supporting TRPV4 research and shed light on potential therapeutic targets for modulating TRPV4-induced calcium oscillation to promote tissue repair while reducing tissue fibrosis.

Mucopolysaccharidosis IVA: Current Disease Models and Drawbacks.

Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) encoding gene. GALNS leads to the lysosomal degradation of the glycosaminoglyccreasans keratan sulfate and chondroitin 6-sulfate. Impaired GALNS enzymes result in skeletal and non-skeletal complications in patients. For years, the MPS IVA pathogenesis and the assessment of promising drugs have been evaluated using in vitro (primarily fibroblasts) and in vivo (mainly mouse) models. Even though value information has been raised from those studies, these models have several limitations. For instance, chondrocytes have been well recognized as primary cells affected in MPS IVA and responsible for displaying bone development impairment in MPS IVA patients; nonetheless, only a few investigations have used those cells to evaluate basic and applied concepts. Likewise, current animal models are extensively represented by mice lacking GALNS expression; however, it is well known that MPS IVA mice do not recapitulate the skeletal dysplasia observed in humans, making some comparisons difficult. This manuscript reviews the current in vitro and in vivo MPS IVA models and their drawbacks.

Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer's disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes in vitro. Here, a three-dimensional Alzheimer's disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network of the human blood-brain barrier with neurospheres derived from Alzheimer's disease-specific neural progenitor cells. To shorten microfluidic co-culture times, neurospheres were pre-differentiated for 21days to express Alzheimer's disease-specific pathological phenotypes prior to the introduction into the microfluidic device. In agreement with post-mortem studies and Alzheimer's disease in vivo models, after 7days of co-culture with pre-differentiated Alzheimer's disease-specific neurospheres, the three-dimensional blood-brain barrier network exhibited significant changes in barrier permeability and morphology. Furthermore, vascular networks in co-culture with Alzheimer's disease-specific microtissues displayed localized β-amyloid deposition. Thus, by interconnecting a microvascular network of the blood-brain barrier with pre-differentiated neurospheres the presented model holds immense potential for replicating key neurovascular phenotypes of neurodegenerative disorders in vitro.

A disease model predicting placebo response and remission status of patients with ulcerative colitis using modified Mayo score.

The Mayo Clinical Score is used in clinical trials to describe the clinical status of patients with ulcerative colitis (UC). It comprises four subscores: rectal bleeding (RB), stool frequency (SF), physician's global assessment, and endoscopy (ENDO). According to recent US Food and Drug Administration guidelines (Ulcerative colitis: developing drugs for treatment, Guidance Document, https://www.fda.gov/regulatory-information/s. 2022), clinical response and remission should be based on modified Mayo Score (mMS) relying on RB, SF, and ENDO. Typically, ENDO is performed at the beginning and end of each phase, whereas RB and SF are more frequently available. Item response theory (IRT) models allow the shared information to be used for prediction of all subscores at each observation time; therefore, it leverages information from RB and SF to predict ENDO. A UC disease IRT model was developed based on four etrolizumab phase III studies to describe the longitudinal mMS subscores, placebo response, and remission at the end of induction and maintenance. For each subscore, a bounded integer model was developed. The placebo response was characterized by a mono-exponential function acting on all mMS subscores similarly. The final model reliably predicted longitudinal mMS data. In addition, remission was well-predicted by the model, with only 5% overprediction at the end of induction and 3% underprediction at the end of maintenance. External evaluation of the final model using placebo arms from five different studies indicated adequate performance for both longitudinal mMS subscores and remission status. These results suggest utility of the current disease model for informed decision making in UC clinical development, such as assisting future clinical trial designs and evaluations.

Bone/cartilage organoid on-chip: Construction strategy and application.

The necessity of disease models for bone/cartilage related disorders is well-recognized, but the barrier between ex-vivo cell culture, animal models and the real human body has been pending for decades. The organoid-on-a-chip technique showed opportunity to revolutionize basic research and drug screening for diseases like osteoporosis and arthritis. The bone/cartilage organoid on-chip (BCoC) system is a novel platform of multi-tissue which faithfully emulate the essential elements, biologic functions and pathophysiological response under real circumstances. In this review, we propose the concept of BCoC platform, summarize the basic modules and current efforts to orchestrate them on a single microfluidic system. Current disease models, unsolved problems and future challenging are also discussed, the aim should be a deeper understanding of diseases, and ultimate realization of generic ex-vivo tools for further therapeutic strategies of pathological conditions.

Who Gets the Flu? Individualized Validation of Influenza-like Illness in Urban Spaces.

Urban dwellers are exposed to communicable diseases, such as influenza, in various urban spaces. Current disease models are able to predict health outcomes at the individual scale but are mostly validated at coarse scales due to the lack of fine-scaled ground truth data. Further, a large number of transmission-driving factors have been considered in these models. Because of the lack of individual-scaled validations, the effectiveness of factors at their intended scale is not substantiated. These gaps significantly undermine the efficacy of the models in assessing the vulnerability of individuals, communities, and urban society. The objectives of this study are twofold. First, we aim to model and, most importantly, validate influenza-like illness (ILI) symptoms at the individual scale based on four sets of transmission-driving factors pertinent to home-work space, service space, ambient environment, and demographics. The effort is supported by an ensemble approach. For the second objective, we investigate the effectiveness of the factor sets through an impact analysis. The validation accuracy reaches 73.2-95.1%. The validation substantiates the effectiveness of factors pertinent to urban spaces and unveils the underlying mechanism that connects urban spaces and population health. With more fine-scaled health data becoming available, the findings of this study may see increasing value in informing policies that improve population health and urban livability.

Non-alcoholic Fatty Liver Disease: Pathology, Disease Models and Therapies

Non-alcoholic fatty liver disease (NAFLD) is characterized by a range of conditions induced through fat accumulation in the liver. This disease impacts population all around the world. NAFLD prevalence is rising at an alarming rate over the past years. To address the alarming increase in NAFLD prevalence, researchers are attempting to develop effective therapeutics to combat NAFLD. To develop NAFLD therapeutics, it is crucial to address current knowledge in NAFLD pathogenesis. Through summarizing current knowledge in NAFLD pathogenesis, researchers can better visualize current knowledge surrounding the disease and present knowledge gaps in the field. This review aims to deeply understand the role of three key NAFLD pathogenic factors: hepatic lipotoxicity, hepatic inflammation, and insulin resistance, and proposes potential target for NAFLD treatment. Furthermore, this review systematically summarizes current disease models and NAFLD therapies. In general, this review provides an overview of the progress of NAFLD and discusses reliable and practical models of NAFLD.

Longitudinal characterization of clinically relevant haemodynamics in conscious Ossabaw pigs with HFpEF

Abstract Background The constantly growing population of patients suffering from heart failure with preserved ejection fraction (HFpEF) is one of the largest unmet needs in cardiovascular medicine and translational animal models are important for identification and profiling of novel therapeutic approaches. Large animal models have shown that chronic cardiac pressure overload by aortic banding (AoB), when combined with a Western diet leads to left ventricular hypertrophy, diastolic dysfunction and metabolic syndrome in the Ossabaw pig, reflecting important features of human HFpEF characteristics. However, the requirement of invasive diagnostics under anaesthesia often limits the ability to monitor disease development continuously and compromises the results. Therefore, current disease models lack the temporal progression of clinically relevant HFpEF parameters like the left ventricular end diastolic pressure (LVEDP) and time constant of left ventricular relaxation (Tau). Purpose We aim to non-invasively investigate disease progression in Ossabaw pigs exhibiting a cardiometabolic HFpEF phenotype. The longitudinal assessment of LVEDP, Tau and heart rate (HR) should identify a time window to test novel therapeutics. Methods Naive, female Ossabaw pigs were instrumented with telemetric devices followed by AoB to induce chronic cardiac pressure overload. The wound healing and acclimatization period was followed by the start of a Western diet feeding regime to mimic components of the metabolic syndrome. Disease progression was characterized over 9 months by monthly telemetric recordings of LVEDP, Tau and HR and compared to a control (Ctrl) measurement in healthy animals. All animal studies followed the `Principles of laboratory animal care'. Results Compared to Ctrl the LVEDP is significantly elevated already 1 month (+8.90±0.4 mmHg) after AoB and further increases over time until 8 months (+18.80±0.4 mmHg) post AoB. Significant elevations in Tau are evident 4 months (+1.61±0.4 ms) post AoB. After 1 month the HR is significantly elevated (+13.90±0.7 bpm) but tends to normalize between 5 to 7 months post AoB. After AoB a maximal relative increase in LVEDP (+5.12±0.4 mmHg), Tau (+5.04±0.4 ms) and HR (+16.90±0.7 bpm) can be observed after 8 months. Conclusions We present long term haemodynamic changes over time in a translational in vivo model for HFpEF in Ossabaw pigs with high temporal resolution. For the first time elevations in key parameters allow to set a time point where HFpEF characteristics are evident, and a drug testing regime could be started. The opportunity to non-invasively and longitudinally follow on LVEDP, Tau and HR will be a clear benefit in the development of novel treatment options for HFpEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG, Wuppertal

Recent Update on Immunopathogenesis of Psoriasis.

Psoriasis is a chronic disabling complex inflammatory disorder prevalent worldwide with environmental and genetic components that involve predominantly skin in addition to nails and joints associated with various systemic comorbidities having periods of exacerbations and remissions. Psoriasis is characterized by hyper-proliferation as well as abnormal differentiation of epidermal keratinocytes and lymphocyte infiltration (mainly T cells) with resultant inflammatory cytokines and chemokines. Immunological and genetic studies over the last decade have identified genetic susceptibility risk alleles, molecular, cellular and immunological mechanisms involved in immunopathogenesis of psoriasis. The current disease model emphasizes the role of aberrant Th1 and Th17 responses regulated by a complex network of different cytokines, including TNF-α, IL-17 and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors and signal transducer and activator of transcriptions. Cytokines targeting biologics (IL-17, IL-23 and TNFα) therapies have revolutionized the management of severe skin disease having beneficial effects on joints and systemic inflammation of psoriasis as well. Further better understanding of immunopathogenesis of psoriasis will pave way for precision medicine based on specific immunopathogenic targets in a given phenotype of disease. Complex interplay of psoriasis with associated comorbidities is also a future area of research for overall better patient management and to improve their quality of life.

A qualitative study exploring how young people perceive and experience substance use services in British Columbia, Canada

BackgroundSubstance use among youth (ages 12–24) is troublesome given the increasing risk of harms associated. Even more so, substance use services are largely underutilized among youth, most only accessing support when in crisis. Few studies have explored young people’s help-seeking behaviours to address substance use concerns. To address this gap, this study explored how youth perceive and experience substance use services in British Columbia (BC), Canada.MethodsParticipatory action research methods were used by partnering with BC youth (under the age of 30) from across the province who have lived and/or living experience of substance use to co-design the research protocol and materials. An initial focus group and interviews were held with 30 youth (ages 12–24) with lived and/or living experience of substance use, including alcohol, cannabis, and illicit substances. The discussions were audio-recorded, transcribed verbatim, and analyzed thematically using a data-driven approach.ResultsThree main themes were identified and separated by phase of service interaction, starting with: Prevention/Early intervention, where youth described feeling unworthy of support; Service accessibility, where youth encountered many barriers finding relevant substance use services and information; and Service delivery, where youth highlighted the importance of meeting them where they are at, including supporting those who have milder treatment needs and/or do not meet the diagnosis criteria of a substance use disorder.ConclusionsOur results suggest a clear need to prioritize substance use prevention and early interventions specifically targeting youth and young adults. Youth and peers with lived and/or living experience should be involved in co-designing and co-delivering such programs to ensure their relevance and credibility among youth. The current disease model of care leaves many of the needs of this population unmet, calling for a more integrated youth-centred approach to address the multifarious concerns linked to young people’s substance use and service outcomes and experiences.

Complement C1q Binding Protein (C1QBP): Physiological Functions, Mutation-Associated Mitochondrial Cardiomyopathy and Current Disease Models

Complement C1q binding protein (C1QBP, p32) is primarily localized in mitochondrial matrix and associated with mitochondrial oxidative phosphorylative function. C1QBP deficiency presents as a mitochondrial disorder involving multiple organ systems. Recently, disease associated C1QBP mutations have been identified in patients with a combined oxidative phosphorylation deficiency taking an autosomal recessive inherited pattern. The clinical spectrum ranges from intrauterine growth restriction to childhood (cardio) myopathy and late-onset progressive external ophthalmoplegia. This review summarizes the physiological functions of C1QBP, its mutation-associated mitochondrial cardiomyopathy shown in the reported available patients and current experimental disease platforms modeling these conditions.

Joint-on-chip platforms: entering a new era of in vitro models for arthritis.

Arthritis affects millions of people worldwide. With only a few disease-modifying drugs available for treatment of rheumatoid arthritis and none for osteoarthritis, a clear need exists for new treatment options. Current disease models used for drug screening and development suffer from several disadvantages and, most importantly, do not accurately emulate all facets of human joint diseases. A humanized joint-on-chip (JoC) model or platform could revolutionize research and drug development in rheumatic diseases. A JoC model is a multi-organ-on-chip platform that incorporates a range of engineered features to emulate essential aspects and functions of the human joint and faithfully recapitulates the joint's physiological responses. In this Review, we propose an architecture for such a JoC platform, discuss the status of the engineering of individual joint tissues and the efforts to combine them in a functional JoC model and identify unresolved issues and challenges in constructing an accurate, physiologically relevant system. The goal is to ultimately obtain a reliable and ready-to-use humanized model of the joint for studying the pathophysiology of rheumatic diseases and screening drugs for treatment of these conditions.

High Throughput Small Molecule Screen for Reactivation of FMR1 in Fragile X Syndrome Human Neural Cells.

Fragile X syndrome (FXS) is the most common inherited cause of autism and intellectual disability. The majority of FXS cases are caused by transcriptional repression of the FMR1 gene due to epigenetic changes that are not recapitulated in current animal disease models. FXS patient induced pluripotent stem cell (iPSC)-derived gene edited reporter cell lines enable novel strategies to discover reactivators of FMR1 expression in human cells on a much larger scale than previously possible. Here, we describe the workflow using FXS iPSC-derived neural cell lines to conduct a massive, unbiased screen for small molecule activators of the FMR1 gene. The proof-of-principle methodology demonstrates the utility of human stem-cell-based methodology for the untargeted discovery of reactivators of the human FMR1 gene that can be applied to other diseases.

ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models.

X-linked adrenoleukodystrophy (X-ALD) is a phenotypically heterogeneous disorder involving defective peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs), due to mutation in the ABCD1 gene. X-ALD is the most common peroxisomal inborn error of metabolism and confers a high degree of morbidity and mortality. Remarkably, a subset of patients exhibit a cerebral form with inflammatory invasion of the central nervous system and extensive demyelination, while in others only dying-back axonopathy or even isolated adrenal insufficiency is seen, without genotype-phenotype correlation. X-ALD's biochemical signature is marked elevation of VLCFAs in blood, a finding that has been utilized for massive newborn screening for early diagnosis. Investigational gene therapy approaches hold promises for improved outcomes. However, the pathophysiological mechanisms of the disease remain poorly understood, limiting investigation of targeted therapeutic options. Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage. Most strikingly, however, cerebral invasion of leukocytes and demyelination were not observed in any animal model for X-ALD, reflecting upon pathological processes that are yet to be discovered. This review summarizes the current disease models in animals, the lessons learned from these models, and the gaps that remained to be filled in order to assist in therapeutic investigations for ALD.

An Empirical Investigation of the Relationship Between Spirituality, Work Culture, and Burnout: The Need for an Extended Health and Disease Model.

Apart from biological, psychological, and social factors, recent studies indicate that spirituality and work culture also play an important role in the onset of burnout. Hence, the commonly applied bio-psycho-social model of health and disease might not be sufficient to comprehensively explain and describe burnout. This study empirically investigates the relationship between spirituality (operationalized by perceived meaningfulness of work) and work culture (operationalized by sense of homeliness of the working environment) with burnout risk and work engagement. For this purpose, an anonymous cross-sectional data collection with fully standardized questionnaires and selected socio-demographic and work-related items was conducted among working adults (n = 439) from different industries via social media and local health service centers. For all scales and subscales, we found significant moderate to strong correlations. Furthermore, positive meaning within the perceived meaningfulness of work scale was the largest beta coefficient for burnout (β = −0.65) and work engagement (β = 0.62). Within sense of homeliness, the largest beta coefficient for burnout was needs fulfillment (β = −0.34) and work engagement emotional connection (β = 0.36). The strong associations suggest that the current health and disease model needs to be expanded to a bio-psycho-socio-spirito-cultural model to be able to sufficiently describe burnout. The perceived meaningfulness of work and a sense of homeliness should be adequately considered when examining the onset of burnout, describing burnout as a concept, and explaining work engagement.

Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis.

Psoriasis, a complex inflammatory autoimmune skin disorder that affects 2–3% of the global population, is thought to be genetically predetermined and induced by environmental and immunological factors. In the past decades, basic and clinical studies have significantly expanded knowledge on the molecular, cellular, and immunological mechanisms underlying the pathogenesis of psoriasis. Based on these pathogenic mechanisms, the current disease model emphasizes the role of aberrant Th1 and Th17 responses. Th1 and Th17 immune responses are regulated by a complex network of different cytokines, including TNF-α, IL-17, and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors (IRFs), and signal transducer and activator of transcriptions (STATs). The biologics developed to specifically target the cytokines have achieved a better efficacy and safety for the systemic management of psoriasis compared with traditional treatments. Nevertheless, the current therapeutics can only alleviate the symptoms; there is still no cure for psoriasis. Therefore, the development of more effective, safe, and affordable therapeutics for psoriasis is important. In this review, we discussed the current trend of therapeutic development for psoriasis based on the recent discoveries in the immune modulation of the inflammatory response in psoriasis.