NOS2-derived low levels of NO drive psoriasis pathogenesis.

Psoriasis is an IL-23/Th17-mediated skin disorder with a strong genetic predisposition. The impact of its susceptibility gene nitric oxide synthase 2 (NOS2) remains unknown. Here, we demonstrate strong NOS2 mRNA expression in psoriatic epidermis, an effect that is IL-17 dependent. However, its complete translation to protein is prevented by the IL-17-induced miR-31 implying marginally upregulated NO levels in psoriatic skin. We demonstrate that lower levels of NO, as opposed to higher levels, increase keratinocyte proliferation and mediate IL-17 downstream effects. We hypothesized that the psoriatic phenotype may be alleviated by either eliminating or increasing cellular NO levels. In fact, using the imiquimod psoriasis mouse model, we found a profound impact on the psoriatic inflammation in both IMQ-treated NOS2 KO mice and wild-type mice treated with IMQ and the NO-releasing berdazimer gel. In conclusion, we demonstrate that IL-17 induces NOS2 and fine-tunes its translation towards a window of proinflammatory and hyperproliferative effects and identify NO donor therapy as a new treatment modality for psoriasis.

Recent developments of P-glycoprotein inhibitors and its structure-activity relationship (SAR) studies.

P-glycoprotein (P-gp) over-expression is a key factor in multi-drug resistance (MDR), which is a major factor in the failure of cancer treatment. P-gp inhibitors have been demonstrated to have powerful pharmacological properties and may be used as a therapeutic approach to overcome the MDR in cancer cells. Combining clinical investigations with biochemical and computational research may potentially lead to a clearer understanding of the pharmacological properties and the mechanisms of action of these P-gp inhibitors. The task of turning these discoveries into effective therapeutic candidates for a variety of malignancies, including resistant and metastatic kinds, falls on medicinal chemists. A variety of P-gp inhibitors with great potency, high selectivity, and minimal toxicity have been identified in recent years. The latest advances in drug design, characterization, structure-activity relationship (SAR) research, and modes of action of newly synthesized, powerful small molecules P-gp inhibitors over the previous ten years are highlighted in this review. P-gp transporter over-expression has been linked to MDR, therefore the development of P-gp inhibitors will expand our understanding of the processes and functions of P-gp-mediated drug efflux, which will be helpful for drug discovery and clinical cancer therapies.

A simple cost-effective microfluidic platform for rapid synthesis of diverse metal nanoparticles: A novel approach towards fighting SARS-CoV-2.

The latest addition to the family of Coronaviruses, SARS-CoV-2, unleashed its wrath across the globe. The outbreak has been so rapid and widespread that even the most developed countries are still struggling with ways to contain the spread of the virus. The virus began spreading from Wuhan in China in December 2019 and has currently affected more than200 countries worldwide. Nanotechnology has huge potential for killing viruses as severe as HIV, herpes, human papilloma virus, and viruses of the respiratory tract, both inside as well as outside the host. Metal-nanoparticles can be employed for biosensing methodology of viruses/bacteria, along with the development of novel drugs and vaccines for COVID-19 and future pandemics. It is thus required for the nanoparticles to be synthesized quickly along with precise control over their size distribution. In this study, we propose a simple microfluidic-reactor-platform for in-situ metal-nanoparticle synthesis to be used against the pandemic for the development of preventive, diagnostic, and antiviral drug therapies. The device has been fabricated using a customized standard photolithography process using a simple and cost-effective setup. The confirmation on standard silver and gold metal nanoparticle formation in the microfluidic reactor platform was analysed using optical fiber spectrophotometer. This novel microfluidic platform provides the advantage of in-situ synthesis, flow parameter control and reduced agglomeration of nanoparticles over the bulk synthesis due to segregation of nucleation and growth stages inside a microchannel. The results are highly reproducible and hence scaling up of the nanoparticle production is possible without involving complex instrumentation.

3D-Printed Impedance Micropump for Continuous Perfusion of the Sample and Nutrient Medium Integrated with a Liver-On-Chip Prototype.

In recent decades, organ-on-chip devices have gained substantial interest as an alternative for studying the pathophysiological processes relevant to drug screening. Micropumps are being utilized to simulate the in vivo physiological fluid flow more realistically in these organ-on-chip devices. Micropumps play a crucial role in pumping, perfusion, and circulation of fluids in various microdevices such as on-chip PCR, DNA microarrays, miniature bioreactor cell separation, and lab-on-chip biosensing platforms. With the rapid growth in technology, efficient pumping for proper circulation of media and nutrients has become imperative. In this study, we have described the design and development of an open-source impedance micropump for continuous perfusion of nutrient medium in a liver-on-chip prototype. This micropump is controlled via an integrated microcontroller board, with an observed flow rate ranging from 0.2 to 2 mL/min. Google Sketchup 2020 and DLP 3D printing were used to fabricate small precise parts of the impedance micropump. The flow rate was measured to characterize the actuating performance of the micropump. The poly-dimethyl siloxane-based liver-on-chip prototype has been fabricated using a soft photolithography procedure. Further, a study of continuous perfusion of culture medium through the liver-on-chip containing the Hepg2 cell line was successfully performed by integrating it with the impedance micropump. Hoechst staining and Alamar Blue observed cell viability to confirm the healthy cell growth inside the liver-on-chip microfluidic chip. The compactness of the overall setup allows it to fit in a Petri plate, eliminating chances of contamination while cell handling.

A Novel Framework for Abnormal Risk Classification over Fetal Nuchal Translucency Using Adaptive Stochastic Gradient Descent Algorithm.

In most maternity hospitals, an ultrasound scan in the mid-trimester is now a standard element of antenatal care. More fetal abnormalities are being detected in scans as technology advances and ability improves. Fetal anomalies are developmental abnormalities in a fetus that arise during pregnancy, birth defects and congenital abnormalities are related terms. Fetal abnormalities have been commonly observed in industrialized countries over the previous few decades. Three out of every 1000 pregnant mothers suffer a fetal anomaly. This research work proposes an Adaptive Stochastic Gradient Descent Algorithm to evaluate the risk of fetal abnormality. Findings of this work suggest that proposed innovative method can successfully classify the anomalies linked with nuchal translucency thickening. Parameters such an accuracy, recall, precision, and F1-score are analyzed. The accuracy achieved through the suggested technique is 98.642.%.

The use of virtual complementary and integrative therapies by neurology outpatients: An exploratory analysis of two cross-sectional studies assessing the use of technology as treatment in an academic neurology department in New York City.

Background: Prior to the COVID-19 pandemic, about half of patients from populations that sought care in neurology tried complementary and integrative therapies (CITs). With the increased utilization of telehealth services, we sought to determine whether patients also increased their use of virtual CITs. Methods: We examined datasets from two separate cross-sectional surveys that included cohorts of patients with neurological disorders. One was a dataset from a study that examined patient and provider experiences with teleneurology visits; the other was a study that assessed patients with a history of COVID-19 infection who presented for neurologic evaluation. We assessed and reported the use of virtual (and non-virtual) CITs using descriptive statistics, and determined whether there were clinical characteristics that predicted the use of CITs using logistic regression analyses. Findings: Patients who postponed medical treatment for non-COVID-19-related problems during the pandemic were more likely to seek CITs. Virtual exercise, virtual psychotherapy, and relaxation/meditation smartphone applications were the most frequent types of virtual CITs chosen by patients. In both studies, age was a key demographic factor associated with mobile/virtual CIT usage. Interpretations: Our investigation demonstrates that virtual CIT-related technologies were utilized in the treatment of neurologic conditions during the pandemic, particularly by those patients who deferred non-COVID-related care.

Assessment of Smartphone Apps for Common Neurologic Conditions (Headache, Insomnia, and Pain): Cross-sectional Study.

BACKGROUND: There are thousands of apps for individuals struggling with headache, insomnia, and pain, but it is difficult to establish which of these apps are best suited for patients' specific needs. If clinicians were to have access to a platform that would allow them to make an informed decision on the efficacy and feasibility of smartphone apps for patient care, they would feel confident in prescribing specific apps. OBJECTIVE: We sought to evaluate the quality of apps for some of the top common, disabling neurologic conditions (headache, insomnia, and pain) based on principles derived from the American Psychiatric Association's (APA) app evaluation model. METHODS: We used the Mobile Health Index and Navigation database and expanded upon the database's current supported conditions by adding 177 new app entries. Each app was rated for consistency with the APA's app evaluation model, which includes 105 objective questions based on the following 5 major classes of consideration: (1) accessibility, (2) privacy and security, (3) clinical foundation, (4) engagement style, and (5) interoperability. These characteristics were evaluated to gain a broader understanding of the significant features of each app category in comparison against a control group. RESULTS: Approximately 90% (187/201) of all apps evaluated were free to download, but only 50% (63/201) of headache- and pain-related apps were truly free. Most (87/106, 81%) sleep apps were not truly free to use. The apps had similar limitations with limited privacy, accessibility, and crisis management resources. For example, only 17% (35/201) of the apps were available in Spanish. The apps offered mostly self-help tools with little tailoring; symptom tracking was the most common feature in headache- (32/48, 67%) and pain-related apps (21/47, 45%), whereas mindfulness was the most common feature in sleep-related apps (73/106, 69%). CONCLUSIONS: Although there are many apps for headache, pain, and insomnia, all 3 types of apps have room for improvement around accessibility and privacy. Pain and headache apps share many common features, whereas insomnia apps offer mostly mindfulness-based resources. Given the many available apps to pick from, clinicians and patients should seek apps that offer the highest-quality features, such as complete privacy, remedial features, and the ability to download the app at no cost. These results suggest that there are many opportunities for the improvement of apps centered on headache, insomnia, and pain.

Cost-effective microabsorbance detection based nanoparticle immobilized microfluidic system for potential investigation of diverse chemical contaminants present in drinking water.

The measurement of the concentration of different heavy-metal ions present in the water environments is becoming increasingly essential as water-pollution concerns worsen. The optical sensor has become a good platform for detecting heavy-metal-ion concentration due to its compact size; chemical inertness; and anti-electromagnetic interference. Here, we propose to fabricate a simple and cost-effective microfluidic device for the detection of aqueous-heavy-metal ions such as lead(II), chromium(III) and mercury(II) using an optical-micro-absorbance-spectroscopy/LSPR based principle. Firstly, a disposable-PDMS-micro-device with a rectangular "Z-shaped microfluidic channel" integrated with micro-lens-structure and optical-fibre-coupler-structure was fabricated via cost-effective soft-lithography-technique using a microfabricated SU8 master. Further, the synthesized-Silver-Nanoparticles were also immobilized inside the microchannel structure in some of the micro-devices for nanoparticle-based-sensing studies. The real-time presence of heavy metal ions in the minuscule sample volume was analyzed by passing different-sample concentrations intermittently through the abovementioned microfluidic structure and measuring the bulk-micro-absorbance across its enhanced optical path length coupler-structure. The results specify that the fabricated micro-device can be easily utilized for label-free detection of a minimum of 0.5 ppb for all the aforesaid sample-heavy metal ions. The absorbance-change observed per unit concentration-change of Lead ion, mercury ion and chromium ion (from 0.001 to ∼50 µg/ml) is found on average-1.8 × 10-2 ΔA/µg/ml, 1.1 × 10-2 ΔA/µg/ml, 4.2 × 10-3 ΔA/µg/ml, respectively. For silver nanoparticle-based studies, the absorbance-change observed per unit concentration change of aforesaid heavy-metal-ions (i.e. the sensitivity) was found on average ∼2 times higher in comparison to simple micro-absorbance-based studies. Additionally, the micro-device has a capability for simplistic incessant(real-time)investigation, a preset-analyte-quantity-interface, and management over the injected analyte-evaporation.

Bilateral Proptosis in a Child-A Rare Manifestation of Ventriculoperitoneal Shunt Obstruction.

Ventriculoperitoneal shunt (VPS) obstruction may have a myriad of presentations. We reported a case of an 11-year-old girl presenting with acute, bilateral proptosis secondary to VPS obstruction. While neuroimaging was interpreted as unremarkable, fundoscopy revealed bilateral papilledema and lumbar puncture showed elevated intracranial pressure. Neurosurgical exploration demonstrated VPS valve obstruction and a new VPS was inserted. Postoperatively, she developed a recurrent extradural hematoma, which was initially evacuated and later managed conservatively. To our knowledge, this is the first report of bilateral proptosis secondary to VPS obstruction. This case highlights the value of key clinical findings and limitations of neuroimaging.

MTH1 Inhibitors for the Treatment of Psoriasis.

Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17‒associated cytokines in the skin, which was in line with decreased levels of IL-17-producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17‒downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application as a promising therapeutic approach to psoriasis.

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation.

Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1ß and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-α was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-α was found to signal through the TNFR‒caspase-8‒caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1ß and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-α-mediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk‒reducing effect.

Amalgamation of diverse hydrodynamic effects with novel triple-sided membrane valves for developing a microfluidic device for filterless and continuous water purification.

The requirement for clean water has been increasing for several reasons, for instance, the fast industrialization of developing countries, climate change, environmental pollution, growth of biofuel use and the resulting growth in irrigation. To meet the requirements for contamination-free water, a cost-effective water treatment can substantially improve the developing world's health, largely for children, and there is predicted to be a huge market for this. Existing water treatment processes consist of various phases that are time-consuming as well as pricey. There is an essential demand for cost-effective point of use methods to purify drinking water to reduce the impact of diseases induced by numerous waterborne pathogens. The development of micro-devices, with different outcomes, can be a helpful solution to various problems. To make this reality, a novel microfluidic device for the purification of water, with multiple hydrodynamic effects, has been shown in this paper. In the proposed novel device, the network of interconnected microfluidic channels was created in such a way that an amalgamation of multiple effects, such as the Fåhræus effect, centrifugal force, the Zweifach-Fung effect and constriction followed by expansion, act together in the microchannel to separate suspended impurities (i.e. bacteria and similar length scale particles present in water in the suspension form) from water. Furthermore, to improve the bacterial separation efficiency of the device, the pure water channel of the microdevice was designed with an encircled triple-sided film valve arrangement at a few points, which aided the modulation of the cross-sectional area of the pure water channel. Consecutively, the reduction of the cross-sectional area of the pure water channel caused a highly effective Zweifach-Fung effect, which aided the better separation of the suspended particles (i.e. bacteria, dust particles etc.). The device was observed to have an average of 99.6% efficiency in the separation of suspended microparticles/microbes with dimensions in the range of 1-10 micrometres. The device performance indicated its potential for the separation of other similar suspended impurities, i.e. small dust particles, bacteria, fungi, viruses and similar particles present in water in the suspension form.

Cost-effective smart microfluidic device with immobilized silver nanoparticles and embedded UV-light sources for synergistic water disinfection effects.

A novel microfluidic-device for water disinfection via diverse physiochemical effects has been demonstrated. Firstly, a microfluidic device with embedded, multiple germicidal UV-LEDs was fabricated through the innovatively modified cost-effective soft-lithography process. Further, synthesised silver nanoparticles were immobilized within its inner microchannel surface. Disinfection results proved the synergistic bactericidal effect of coated AgNPs and coupled UV-light, while a suspension of bacterial strains, were passed through the micro-device.

Prototype of a Smart Microfluidic Platform for the Evaluation of SARS-Cov-2 Pathogenesis, Along with Estimation of the Effectiveness of Potential Drug Candidates and Antigen-Antibody Interactions in Convalescent Plasma Therapy.

Originating in China during December 2019, the novel corona-virus, SARS-CoV-2, has created mayhem worldwide in a very short time. The outbreak has been so rapid and widespread that the only option to treat the patients was administering drugs already available in the market like chloroquine/hydroxychloroquine (an antimalarial drug) and remedesivir. A large number of patients have been cured but the attribution to survival by these drugs has been controversial. Till date, we do not have any specific drug or vaccine available for COVID-19 and the pandemic seems to be far from over. To handle the current challenges posed by the outbreak effectively, we need to employ innovative interdisciplinary approaches. Organ-on-chip (OOC), particularly lung-on-chip, is one such approach which combines the potential of microfluidics, cell culture and molecular biology into a single miniaturised platform. The device is realized to be capable of simulating in-vivo physiological responses of an organ. In the current study, an OOC, which is a multichannel 3D cell culture microfluidic device, is made via soft lithography technique, using polydimethylsiloxane-polymer and diverse polymeric porous/semipermeable membranes. Several polymer membranes i.e. PDMS, polyvinylidene fluoride (PVDF), nitrocellulose, polyester etc., integrated into the microdevices, were efficiently explored to realize their better cell-adhesion and viability property. We also propose for the application of a simple, smart and cost-effective lung-on-chip platform to study the SARS-CoV-2 pathogenesis in humans, drug toxicity testing and provide insights into antigen-antibody interactions. This platform will enable us to study multiple phenomena at a micro-level generating more reliable data and a better understanding of the underlying mechanisms of SARS-CoV-2 infection and pathogenesis.

Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naïve subjects.

The protection against tuberculosis induced by the Bacille Calmette Guérin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively ('responders'). These macrophages also showed production of Interleukin-1ß (IL-1ß) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1ß production, was strongly correlated with the DMG pattern.

Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia.

Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.

Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.

BACKGROUND: In psoriasis, a common immune-mediated disease affecting 2-3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment. OBJECTIVE: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis. METHODS: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response. RESULTS: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10-12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction. CONCLUSION: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens.

OBJECTIVE: (1) The objective is to study the immunohistochemical expression of Breast cancer type 1 (BRCA1) in breast carcinoma on trucut biopsy specimens and (2) To relate its expression with that of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER-2)/neu and the clinicopathological parameters. SETTINGS AND DESIGN: A cross-sectional hospital-based study was performed in Lady Hardinge Medical College and Shrimati Sucheta Kriplani Hospital, New Delhi, with collaboration of the Departments of Pathology and Surgery from the period of November 2008 to March 2010. MATERIALS AND METHODS: The study group included 54 cytologically proven cases of breast carcinoma. The immunohistochemical expression of BRCA1 was studied and related with expression of ER, PR, and HER-2/neu on their trucut biopsies. RESULTS: The altered expression of BRCA1 (i.e., reduced or absent expression) was seen in 44.4% cases of breast carcinoma while 55.6% had positive expression. About 83% of breast carcinomas with altered BRCA1 expression were larger than 3 cm in size. The breast carcinomas showing altered expression were found to be mostly high grade (63.6%). This was statistically significant. The ER and PR negativity were seen in 62.5% and 79.2% breast carcinomas with altered BRCA1 expression, respectively. The score 3 positivity of HER-2/neu was more common among carcinomas with altered BRCA1 expression (21% vs. 16.7%). The triple negativity was found in 41.7% breast carcinomas having altered BRCA1 expression. This was statistically significant. CONCLUSION: The combination of immunohistochemical expression of BRCA1, ER, PR, and HER-2/neu and clinicopathological details may be helpful in predicting the individuals more likely to carry BRCA1 mutations and thus selecting the candidate and family members for genetic screening for BRCA1 mutations.

Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis.

Psoriasis is a chronic inflammatory skin disease with both local and systemic components. Genome-wide approaches have identified more than 60 psoriasis-susceptibility loci, but genes are estimated to explain only one-third of the heritability in psoriasis, suggesting additional, yet unidentified, sources of heritability. Epigenetic modifications have been linked to psoriasis and altered DNA methylation patterns in psoriatic versus healthy skin have been reported in whole-skin biopsies. In this study, focusing on epigenetic modifications in the psoriatic uninvolved skin, we compared the lesional and non-lesional epidermis from psoriasis patients with epidermis from healthy controls. We performed an exhaustive genome-wide DNA methylation profiling using reduced representation bisulfite sequencing, which interrogates the methylation status of approximately 3-4 million CpG sites. More than 2,000 strongly differentially methylated sites were identified and a striking overrepresentation of the Wnt and cadherin pathways among the differentially methylated sites was found. In particular, we observe a strong differential methylation in several psoriasis candidate genes. A substantial number of differentially methylated sites present in the uninvolved versus healthy epidermis suggests the presence of a pre-psoriatic state in the clinically healthy skin type. Our exploratory study represents a starting point for identifying biomarkers for psoriasis-prone skin before disease onset.