Microneedle-mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune-Mediated Alopecia.

Disorders in the regulatory arm of the adaptive immune system result in autoimmune-mediated diseases. While systemic immunosuppression is the prevailing approach to manage them, it fails to achieve long-lasting remission due to concomitant suppression of the regulatory arm and carries the risk of heightened susceptibility to infections and malignancies. Alopecia Areata is a condition characterized by localized hair loss due to autoimmunity. The accessibility of the skin provides an opportunity for local rather than systemic intervention to avoid broad immunosuppression. We hypothesized that expansion of endogenous regulatory T cells (Tregs) at the site of antigen encounter can restore the immune balance and generate a long-lasting tolerogenic response. We therefore utilized a hydrogel microneedle (MN) patch for delivery of CCL22, a chemoattractant for Tregs, and IL-2, a Treg survival factor to amplify them. In an immune-mediated murine model of alopecia, we showed local bolstering of Treg numbers leading to sustained hair regrowth and attenuation of inflammatory pathways. In a humanized skin transplant mouse model, we confirmed expansion of Tregs within human skin without engendering peripheral immunosuppression. The MN patch offered high-loading capacity and shelf-life stability for prospective clinical translation. By harmonizing immune responses locally, we aspire to reshape the landscape of autoimmune skin disease management. This article is protected by copyright. All rights reserved.

Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.

Background: Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects. Methods: To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions. Results: Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions. Conclusion: Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.

High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma.

Chordomas account for approximately 1-4% of all malignant bone tumors and 20% of primary tumors of the spinal column. It is a rare disease, with an incidence estimated to be approximately 1 per 1,000,000 people. The underlying causative mechanism of chordoma is unknown, which makes it challenging to treat. Chordomas have been linked to the T-box transcription factor T (TBXT) gene located on chromosome 6. The TBXT gene encodes a protein transcription factor TBXT, or brachyury homolog. Currently, there is no approved targeted therapy for chordoma. Here, we performed a small molecule screening to identify small chemical molecules and therapeutic targets for treating chordoma. We screened 3730 unique compounds and selected 50 potential hits. The top three hits were Ribociclib, Ingenol-3-angelate, and Duvelisib. Among the top 10 hits, we found a novel class of small molecules, including proteasomal inhibitors, as promising molecules that reduce the proliferation of human chordoma cells. Furthermore, we discovered that proteasomal subunits PSMB5 and PSMB8 are increased in human chordoma cell lines U-CH1 and U-CH2, confirming that the proteasome may serve as a molecular target whose specific inhibition may lead to better therapeutic strategies for chordoma.

May Measurement Month 2019: an analysis of blood pressure screening results from Lebanon.

Hypertension is an important public health concern of high prevalence among adults. It is associated with an increased mortality rate. The prevalence of hypertension in Lebanon has increased during the last decades, affecting around one-third of the Lebanese population. Since diagnosis and treatment of hypertension is associated with a better prognosis, annual screening and raising awareness about this 'silent killer' disease is of extreme value. We conducted a cross-sectional survey in various Lebanese cities in 2019. We recruited adults (≥18 years old) from different sites, through an opportunistic sampling method. For each participant, three blood pressure (BP) readings were recorded and the average of the last two was analysed. In addition, data on lifestyle factors and comorbidities were collected. Participants were considered hypertensive if they had at least one of the following: systolic or diastolic BP ≥140 and/or ≥90 mmHg, respectively, or taking antihypertensive medication. Blood pressure was measured in 7019 participants. The mean age was 46.0 (SD 16.6) years. In total, 2572 participants (36.6%) had hypertension among whom only 64.1% were aware of their disease and 62.3% were on treatment. Blood pressure was controlled in 62.6% of participants taking antihypertensive medications. This study is the largest on hypertension prevalence in Lebanon. The results demonstrated that around one-third of the hypertensive population were not aware of their disease, and that a high percentage was not being treated. These results suggest the need for rapid interventions aimed at raising awareness regarding hypertension in the Lebanese population.

Subaortic Membrane With Mitral Chordae Rupture Mimicking Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disorder that can lead to left ventricular outflow tract (LVOT) obstruction. Some patients present with syncope, dyspnea, chest pain, or sudden cardiac death. A subaortic membrane (SAM) is an unusual cause of ventricular outflow tract obstruction causing symptoms that can imitate HCM. It is essential to differentiate between these two entities, as it has important implications in guiding treatment and determining the type of intervention. Echocardiography is the gold standard modality for the diagnosis. In this report, we present a case of a 56-year-old man presenting with subaortic stenosis with ruptured mitral chordae misdiagnosed as HCM with SAM.

Role of Echocardiography in the Diagnosis of Light Chain Amyloidosis: A Case Report and Review of Literature.

Amyloid light-chain (AL) amyloidosis is a rare disease with a broad clinical presentation that depends on the affected organ. Cardiac amyloidosis, a rare entity, can present as an isolated form of AL amyloidosis. This isolated form is considered a challenging diagnosis due to its broad nonspecific clinical presentation. In this article, we report a case of an adult male who presented with shortness of breath and was found to have many specific features of cardiac amyloidosis on echocardiography. In absence of other organ involvement, the results of the echocardiography directed us toward the diagnosis of AL cardiac amyloidosis. In addition, we highlight the role of echocardiography in the diagnosis of cardiac amyloidosis.

Hyperthyroidism as a Potential Trigger for Benign Recurrent Intrahepatic Cholestasis.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disease often causing episodes of jaundice since childhood. Its triggering factors are still unknown. Hyperthyroidism solely is an infrequent cause of jaundice, and it was never described in association with BRIC. In this article, we reported a woman presenting with a new episode of BRIC and was found to have concomitant hyperthyroidism in the absence of any other potential trigger factor. We conclude that hyperthyroidism may trigger cholestasis in patients with BRIC.

Anti-Glomerular Basement Membrane Disease as a Potential Complication of COVID-19: A Case Report and Review of Literature.

Since the COVID-19 outbreak has started, many reports showed that COVID-19 does not affect only the respiratory system but can alter multiple organs including kidneys. Anti-glomerular basement membrane disease (anti-GBM) is a systemic disease affecting mainly kidneys and lungs. It can sometimes be triggered by a respiratory infection such as influenza however the mechanism is not clear yet. We describe a novel case of Anti-GBM disease possibly complicating COVID-19. We report a case of a 63-year-old man who was admitted to our hospital for fever and myalgia and was found to have COVID-19. During hospitalization, he developed kidney injury along with pulmonary hemorrhage and was found to have anti-GBM antibodies. Our patient was treated as a case of Anti-GBM disease potentially triggered by COVID-19. Hence, the anti-GBM disease could be a potential complication of COVID-19.