Hemophagocytic Lymphohistiocytosis Syndrome With Hepatic Involvement and Secondary to Acute B-cell Lymphocytic Leukemia: A Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperactivation syndrome associated with the overactivation of macrophages, which produce enormous amounts of tumor necrosis factor-alpha and interferon-gamma. HLH often presents with diminished T-cell and natural killer (NK) cell regulation, which can develop due to underlying genetic causes, infections, autoimmune diseases, and/or secondary to malignancies. Here, we describe the case of a 39-year-old man who presented with subjective fevers and fatigue. Further workup revealed hyperferritinemia, hypertriglyceridemia, and absent NK-cell activity, which raised a strong suspicion for HLH. The workup also revealed elevated aminotransferases signaling hepatic involvement that was attributed to HLH. Bone marrow biopsy revealed hypercellularity instead of the hemophagocytosis usually seen in HLH. Flow cytometry revealed acute B-cell lymphocytic leukemia, which was identified as the cause of HLH in our patient. This case highlights the rare presentation of HLH secondary to a B-cell malignancy. It addresses the importance of high clinical suspicion in patients with high fevers despite the use of broad-spectrum antibiotics. There is limited information on the treatment of HLH secondary to malignancies specifically, and further research in this area is needed to increase the survival rate.

Acute Extensive Deep Vein Thrombosis After Heterogeneous Administration of Moderna mRNA Booster Vaccine: A Case Report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) struck the world in 2019 and led to the development of the multisystem coronavirus disease-2019 (COVID-19) causing a worldwide pandemic. Vaccines with boosters were developed due to novel mutations of SARS-CoV-2. Heterogeneous vaccination emerged with the perception that mixing vaccines can provide better protection. We present the case of a 68-year-old male patient who developed extensive acute deep vein thrombosis (DVT) of the left lower extremity, two weeks following the Moderna mRNA booster vaccine (mRNA-1273). His first two doses were AstraZeneca ChAdOx1-S [recombinant]. He was started on a heparin drip and prescribed rivaroxaban. We discuss the possible etiology of this DVT, the mechanism of action of the Moderna mRNA vaccine, the association of DVT with vaccine-induced inflammation, implications of heterogeneous vaccine combinations, and recommendations to advise people on possible thrombogenic adverse effects prior to mRNA vaccine administration.

Disease-associated mutations in human TUBB3 disturb netrin repulsive signaling.

Missense mutations in the human TUBB3 gene cause a variety of neurological disorders associated with defects in axon guidance and neuronal migration, but the underlying molecular mechanisms are not well understood. Recent studies have shown that direct coupling of dynamic TUBB3 in microtubules with netrin receptors is required for netrin-1-mediated axon guidance, and the interaction of netrin-1 repulsive receptor UNC5C with TUBB3 is involved in netrin-1 mediated axonal repulsion. Here, we report that TUBB3 mutations perturb netrin-1/UNC5C repulsive signaling in the developing nervous system. Among twelve mutants reported in previous studies, five of them show significantly reduced interaction with UNC5C in comparison to the wild-type TUBB3. TUBB3 mutants R262C and R62Q exhibit decreased subcellular colocalization with UNC5C in the peripheral area of the growth cone of primary mouse neurons. Netrin-1 reduces the colocalization of UNC5C with wild-type TUBB3, but not TUBB3 mutants R262C or R62Q, in the growth cone. Results from the in vitro cosedimentation assay indicate that netrin-1 inhibits cosedimentation of UNC5C with polymerized microtubules in primary mouse neurons expressing the wild-type TUBB3, but not R262C or R62Q. Expression of either R262C or R62Q not only blocks netrin-1-induced growth cone collapse and axonal repulsion of primary EGL cells in vitro, but also results in axon projections defects of chicken dorsal root ganglion neurons in ovo. Our study reveals that human TUBB3 mutations specifically perturb netrin-1/UNC5C-mediated repulsion.

Uncoupling of UNC5C with Polymerized TUBB3 in Microtubules Mediates Netrin-1 Repulsion.

Modulation of microtubule (MT) dynamics is a key event of cytoskeleton remodeling in the growth cone (GC) during axon outgrowth and pathfinding. Our previous studies have shown that the direct interaction of netrin receptor DCC and DSCAM with polymerized TUBB3, a neuron-specific MT subunit in the brain, is required for netrin-1-mediated axon outgrowth, branching, and attraction. Here, we show that uncoupling of polymerized TUBB3 with netrin-1-repulsive receptor UNC5C is involved in netrin-1-mediated axonal repulsion. TUBB3 directly interacted with UNC5C and partially colocalized with UNC5C in the peripheral area of the GC of primary neurons from the cerebellar external granule layer of P2 mouse pups of both sexes. Netrin-1 reduced this interaction as well as the colocalization of UNC5C and TUBB3 in the GC. Results from the in vitro cosedimentation assay indicated that UNC5C interacted with polymerized TUBB3 in MTs and netrin-1 decreased this interaction. Knockdown of either TUBB3 or UNC5C blocked netrin-1-promoted axon repulsion in vitro and caused defects in axon projection of DRG toward the spinal cord in vivo Furthermore, live-cell imaging of end-binding protein 3 tagged with EGFP (EB3-GFP) in primary external granule layer cells showed that netrin-1 differentially increased MT dynamics in the GC with more MT growth in the distal than the proximal region of the GC during repulsion, and knockdown of either UNC5C or TUBB3 abolished the netrin-1 effect. Together, these data indicate that the disengagement of UNC5C with polymerized TUBB3 plays an essential role in netrin-1/UNC5C-mediated axon repulsion.SIGNIFICANCE STATEMENT Proper regulation of microtubule (MT) dynamics in the growth cone plays an important role in axon guidance. However, whether guidance cues modulate MT dynamics directly or indirectly is unclear. Here, we report that dissociation of UNC5C and polymerized TUBB3, the highly dynamic ß-tubulin isoform in neurons, is essential for netrin-1/UNC5C-promoted axon repulsion. These results not only provide a working model of direct modulation of MTs by guidance cues in growth cone navigation but also help us to understand molecular mechanisms underlying developmental brain disorders associated with TUBB3 mutations.