Vascular Malformation Involving the Brachial Plexus: A Case Report and Review of Literature.

Introduction: Vascular anomalies, comprising up to 4.5% of the general population, are aberrations occurring during vascular development. Vascular abnormalities are frequently identified in children and frequently exhibit characteristics similar to nerve sheath tumors. We report a case of 16 years old boy with a arterio-venous (AV) malformation (AVM) affecting the brachial plexus. We discuss the clinical features, diagnosis, treatment, and histopathological findings in this patient and review the relevant literature. Case Report: A 16- year-s old boy presented with pain, paresthesia, swelling, and reduced grip strength of the hand. Radiological investigations revealed a vascular lesion encasing C5, C6 nerve roots and displacing the C7 root. Near total surgical excision of the lesion was done with preservation of nerve. Histopathology confirmed arteriovenous AVMmalformation with distinct features. Conclusion: High-resolution ultrasound is crucial for diagnosing soft- tissue vascular anomalies. Surgeons well versed in micro surgical skill play a vital key role in minimizing neural deficits. In the case of vascular malformations of brachial plexus, near total excision is the most favorable option.

Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer.

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer.

Phase transition from nematic to high-density disordered phase in a system of hard rods on a lattice.

A system of hard rigid rods of length k on hypercubic lattices is known to undergo two phase transitions when chemical potential is increased: from a low density isotropic phase to an intermediate density nematic phase, and on further increase to a high-density phase with no orientational order. In this paper, we argue that, for large k, the second phase transition is a first-order transition with a discontinuity in density in all dimensions greater than 1. We show that the chemical potential at the transition is ≈kln[k/lnk] for large k, and that the density of uncovered sites drops from a value ≈(lnk)/k^{2} to a value of order exp(-ak), where a is some constant, across the transition. We conjecture that these results are asymptotically exact, in all dimensions d≥2. We also present evidence of coexistence of nematic and disordered phases from Monte Carlo simulations for rods of length 9 on the square lattice.

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.

Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers.

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier's cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.

Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann-Pick Disease Type C Using Crosslinked 2-Hydroxypropyl-ß-cyclodextrin.

Niemann-Pick disease type C (NPC) is a severe disorder that is characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and sphingolipids. The compound 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HPßCD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) display a ninefold greater cholesterol complexation capacity than monomeric HPßCD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3 kDa HPßCD exhibits a longer half-life than the monomeric HPßCD but it does not increase the life span of Npc1 mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HPßCDs can elucidate CDs' mechanism of action while the use of MRIg-FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.