Guillain-Barre syndrome following subclinical COVID-19 infection in a child.

The entire world is coping up with the challenges imposed by COVID-19 pandemic caused by a novel coronavirus, which started from a single case in Wuhan city of China in November 2019. Its outcomes range from asymptomatic cases to most severe diseases like severe acute respiratory syndrome. Neurological manifestations have also been reported as an outcome of coronavirus infection and Guillain-Barre Syndrome (GBS) is one of them. In our present case, we describe the correlation of GBS with subclinical SARS-CoV-2 in a pediatric patient. The patient was successfully managed with intravenous immunoglobulin and physiotherapy. In the current pandemic, any case of GBS should be evaluated for recent or remote SARS-CoV-2 infection.

Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial.

PURPOSE: Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis. PATIENTS AND METHODS: Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis. RESULTS: In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients. CONCLUSIONS: Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868.

A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice.

T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors.

Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation.

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310-21. ©2017 AACR.

Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases.

Throughout time, plants have often displayed medicinal properties that have been underscored. We often derive medicines involved in treating cancer from components in plants. Azadirachta indica, commonly known as "neem", has been used to treat different ailments in many Asian countries. Due to its widespread beneficial uses, A. indica has often been referred to as "the wonder tree" or "nature's drug store". Various parts of this plant, including, leaves, flowers, fruits, seeds, roots, bark and oil, produce a large number of phytochemicals with various biological and pharmacological activities. The numerous biological activities of the phytoconstituents of A. indica explain its beneficial uses for the prevention and therapy of cancer. The chemopreventive and anticancer therapeutic efficacy of A. indica fractions and compounds could be explained by multiple cellular and molecular mechanisms, including free radical scavenging, carcinogen-detoxification, DNA repair, cell cycle alteration, programmed cell death (apoptosis) and autophagy, immune surveillance, anti-inflammatory, anti-angiogenic, anti-invasive and anti-metastatic activities as well as their ability to modulate several dysregulated oncogenic signaling pathways. This article aims to present the collective and critical analysis of multiple phytoconstituents of A. indica and their molecular mechanisms implicated in cancer chemopreventive and therapeutic effects based on published preclinical and clinical results. Current limitations and future directions of research on this medicinal plant are also critically discussed.