Overcoming Challenges in Chemical Glycosylation to Achieve Innovative Vaccine Adjuvants Possessing Enhanced TLR4 Activity.

Lipopolysaccharide (LPS) mimicry leading to toll-like receptor 4 (TLR4) active compounds has been so far based mainly on reproducing the lipid A portion of LPS. Our work led to a series of structurally simplified synthetic TLR4 agonists in preclinical development as vaccine adjuvants called FPs. FPs bind MD2/TLR4 similarly to lipid A, inserting the lipid chains in the MD2 lipophilic cavity. A strategy to improve FPs' target affinity is introducing a monosaccharide unit in C6, mimicking the first sugar of the LPS core. We therefore designed a panel of FP derivatives bearing different monosaccharides in C6. We report here the synthesis and optimization of FPs' C6 glycosylation, which presented unique challenges and limitations. The biological activity of glycosylated FP compounds was preliminarily assessed in vitro in HEK-Blue cells. The new molecules showed a higher potency in stimulating TLR4 activation when compared to the parent molecule while maintaining TLR4 selectivity.

Acquired bilateral facial palsy: a systematic review on aetiologies and management.

OBJECTIVE: To systematically review the published cases of bilateral facial palsy (BFP) to gather evidence on the clinical assessment and management of this pathology. METHODS: Following PRISMA statement recommendations, 338 abstracts were screened independently by two authors. Inclusion criteria were research articles of human patients affected by BFP, either central or peripheral; English, Italian, French or Spanish language; availability of the abstract, while exclusion criteria were topics unrelated to FP, and mention of unilateral or congenital FP. Only full-text articles reporting the diagnostic work-up, the management, and the prognosis of the BFP considered for further specific data analysis. RESULTS: A total of 143 articles were included, resulting a total of 326 patients with a mean age of 36 years. The most common type of the paralysis was peripheral (91.7%), and the autoimmune disease was the most frequent aetiology (31.3%). The mean time of onset after first symptoms was 12 days and most patients presented with a grade higher than III. Associated symptoms in idiopathic BFP were mostly non-specific. The most frequently positive laboratory exams were cerebrospinal fluid analysis, autoimmune screening and peripheral blood smear, and the most performed imaging was MRI. Most patients (74%) underwent exclusive medical treatment, while a minority were selected for a surgical or combined approach. Finally, in more than half of cases a complete bilateral recovery (60.3%) was achieved. CONCLUSIONS: BFP is a disabling condition. If a correct diagnosis is formulated, possibilities to recover are elevated and directly correlated to the administration of an adequate treatment.

Clear cell sarcoma-like/malignant gastrointestinal neuroectodermal tumor of the tongue: a clinicopathologic and molecular case report.

Malignant gastrointestinal neuroectodermal tumor (M-GNET) and clear cell sarcoma (CCS) of soft tissue represent closely related, extremely rare, malignant mesenchymal neoplasm of uncertain differentiation. Both entities are characterized genetically by the same molecular alterations represented by the presence of EWSR1-ATF1 and, more rarely, EWSR1-CREB1 fusion genes. The latter translocation seems to be more represented in M-GNET that, despite significant morphologic overlap with CCS, tends to lack overt features of melanocytic differentiation. Most M-GNET occur in the lower gastrointestinal tract, whereas occurrence in the upper tract has been reported only exceptionally. The differential diagnosis represents a major challenge, and accurate diagnosis impact significantly on therapeutic planning. We herein report the clinicopathologic features of a molecularly confirmed M-GNET that arose at the base of the tongue and review the pertinent literature.