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Background: Brain metastases in pediatric osteosarcoma are infrequent but associated with a dire prognosis. Methods: This retrospective study examined six pediatric patients at Johns Hopkins Hospital who developed brain metastases from osteosarcoma between April 2015 and November 2023. Results: Median survival post-brain metastasis was 2.5 months. The patients underwent various treatments, including chemotherapy, surgery, and radiation. Despite these interventions, outcomes were uniformly fatal. Notably, one patient survived over 13 months post-brain metastasis with a treatment regimen of cabozantinib and nivolumab along with surgical resection and radiation, highlighting the potential efficacy of multimodal treatment regimens. This case demonstrated changes in the immune microenvironment, hinting at an anti-tumoral response, although no histologic response was observed. Conclusions: These findings emphasize the critical need for vigilant clinical monitoring, especially in patients with new neurological symptoms. The study highlights the diagnostic challenges and the rapid progression of brain metastases, underscoring the necessity for further research. Prospective studies and clinical trials focusing on novel therapeutic strategies are essential to improve outcomes. Disease biology studies examining tumor features across primary, pulmonary, and brain metastatic sites may offer insights into the mechanisms of metastasis and potential therapeutic targets, providing a foundation for better management of this devastating complication.

Cerebrospinal fluid (CSF) biomarkers amyloid-β and tau have been validated for the antemortem diagnosis of Alzheimer disease (AD) and are included in the AT(N) research framework for AD. Recently, an AT(N) CSF profile has been described for dementia with Lewy bodies (DLB), a disorder which is difficult to distinguish clinically from AD, particularly early in the disease course. Herein we describe a 71-year old male who presented with an atypical dementia syndrome including years of stability after an initial abrupt decline, marked visuospatial dysfunction, and relative sparing of memory. CSF biomarkers combined with the pattern of cognitive symptoms made AD unlikely and were consistent with DLB. This classification was confirmed clinically, with the emergence of classic DLB symptoms, and at postmortem pathologic examination. This case highlights the role for AD CSF biomarkers in facilitating earlier diagnosis of non-Alzheimer neurodegenerative dementias.

C-type lectin receptors (CLRs) play key roles in antifungal defense. CLR-induced NF-κB is central to CLR functions in immunity, and thus, molecules that control the amplitude of CLR-induced NF-κB could profoundly influence host defense against fungal pathogens. However, little is known about the mechanisms that negatively regulate CLR-induced NF-κB, and molecules which act on the CLR family broadly and which directly regulate acute CLR-signaling cascades remain unidentified. Here, we identify the ubiquitin-editing enzyme A20 as a negative regulator of acute NF-κB activation downstream of multiple CLR pathways. Absence of A20 suppression results in exaggerated CLR responses in cells which are A20 deficient and also cells which are A20 haplosufficient, including multiple primary immune cells. Loss of a single allele of A20 results in enhanced defense against systemic Candida albicans infection and prolonged host survival. Thus, A20 restricts CLR-induced innate immune responses in vivo and is a suppressor of host defense against systemic fungal infection.

Plants are foundational for global ecological and economic systems, but most plant proteins remain uncharacterized. Protein interaction networks often suggest protein functions and open new avenues to characterize genes and proteins. We therefore systematically determined protein complexes from 13 plant species of scientific and agricultural importance, greatly expanding the known repertoire of stable protein complexes in plants. By using co-fractionation mass spectrometry, we recovered known complexes, confirmed complexes predicted to occur in plants, and identified previously unknown interactions conserved over 1.1 billion years of green plant evolution. Several novel complexes are involved in vernalization and pathogen defense, traits critical for agriculture. We also observed plant analogs of animal complexes with distinct molecular assemblies, including a megadalton-scale tRNA multi-synthetase complex. The resulting map offers a cross-species view of conserved, stable protein assemblies shared across plant cells and provides a mechanistic, biochemical framework for interpreting plant genetics and mutant phenotypes.

T cell development involves extensive proliferation of developing thymocytes. Here, the authors demonstrate that the transcription factor Zfp335 regulates the survival post-β-selection thymocytes via the cGAS/STING pathway.

Background: In the U.S., research to identify the risk factors explaining high rates of adolescent pregnancy disproportionately affecting racial/ethnic minorities, including Latinas, have largely focused on social and cultural factors that influence girls’ pregnancy intentions and decisions regarding the use of contraception, as well as girls’ sexual and reproductive decision-making control in relationships. However, economic factors may play a role in increasing girls’ risk for adolescent pregnancy as well. Disproportionately high rates of adolescent pregnancy occur in areas of concentrated poverty, with higher rates among ethnic minorities. This qualitative study used a descriptive, exploratory design with a content analysis approach (1) to describe economic vulnerability in girls’ lives and (2) to identify potential ways in which economic vulnerability may influence risk factors for adolescent pregnancy among adolescent females at high risk for pregnancy recruited from a health clinic by the U.S.–Mexico border in California. Methods: Qualitative in-depth interviews were conducted among 21 girls reporting risk factors for pregnancy (including a previous pregnancy, experiences of dating violence, or having ever been diagnosed with an STI) and who were seeking sexual/reproductive health services at a clinic near the U.S.–Mexico border in California. Participants were asked about their family life, economic stressors, characteristics of intimate partner relationships, and future education/career aspirations. Interviews were analyzed using content analysis to identify common themes related to economic vulnerability and risk for pregnancy. Results: Female participants were 17 years of age on average, most (72%) were Latina, and over half (60%) were in a relationship. Participants reported a high level of economic vulnerability at home, which they felt compromised their welfare, negatively affected expectations for future educational goals, and promoted financial dependence for basic needs (e.g., food) on male partners. The latter often compromised girls’ decision-making control with relationship partners over contraceptive use and pregnancy timing. Conclusions: Study findings suggest that economic vulnerability: (a) supports economic reliance on male partners, with implications for male partner control over pregnancy decisions and (b) hinders girls’ expectations for future educational opportunities, which may reduce girls’ prioritization to delay pregnancy.

The RASopathies, collectively, are a spectrum of genetic syndromes caused by mutations in genes involved in the RAS/ mitogen-activated protein kinase (MAPK) pathway, including but not limited to PTPN11 , NRAS , KRAS , HRAS , BRAF , and MAP2K1. Recognized RASopathy conditions include neurofibromatosis type 1 (NF1), Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacio-cutaneous (CFC) syndrome, LEOPARD syndrome and Legius syndrome. The RASopathies often display overlapping clinical features, presumably owing to common RAS-MAPK signaling pathway activation driving dysregulated cell proliferation. Epidermal nevus syndromes (ENS) are described as the presence of epidermal nevi, in individuals also affected by extra-cutaneous organ system involvement, and there is recent recognition of mosaic RAS mutations as molecular drivers of ENS. Currently, no curative treatments exist for RASopathy driven conditions, but rather symptom-directed management is the currently accepted standard. Here, we detail a unique case of a child exhibiting diffuse spinal nerve root hypertrophy in the context of epidermal nevus syndrome driven by molecularly confirmed KRAS G12D mosaicism, treated with the MEK 1/2 inhibitor selumetinib. Herein, we report the response of this patient to targeted therapy of more than two years' duration, including stabilization of multilevel nerve root hypertrophy as well as significant improvement in epidermal nevi. While the effectiveness of MEK inhibitors such as selumetinib is established in NF1 -associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS -driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling. [ABSTRACT FROM AUTHOR]

Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer's disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Objective: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ. Methods: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Conclusions: Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD. [ABSTRACT FROM AUTHOR]

Abstract Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely characterized. We measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain (RBD), ACE2 displacement and viral neutralization activities one month following the first and second COVID-19 vaccine doses, and again 3 months following the second dose, in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525–935) cells/mm3, though nadir CD4+ T-cell counts ranged as low as

SARS-CoV-2 Omicron infections are common among individuals who are vaccinated or have recovered from prior variant infection, but few reports have immunologically assessed serial Omicron infections. We characterized SARS-CoV-2 humoral responses in an individual who acquired laboratory-confirmed Omicron BA.1.15 ten weeks after a third dose of BNT162b2, and BA.2 thirteen weeks later. Responses were compared to 124 COVID-19-naive vaccinees. One month post-second and -third vaccine doses, the participant’s wild-type and BA.1-specific IgG, ACE2-displacement and virus neutralization activities were average for a COVID-19-naive triple-vaccinated individual. BA.1 infection boosted the participant’s responses to the cohort ≥95th percentile, but even this strong “hybrid” immunity failed to protect against BA.2. Reinfection increased BA.1 and BA.2-specific responses only modestly. Though vaccines clearly protect against severe disease, results highlight the continued importance of maintaining additional protective measures to counteract the immune-evasive Omicron variant, particularly as vaccine-induced immune responses naturally decline over time.

Inflammation induced by innate immunity influences the development of T cell-mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome-independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4+ T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: “Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD).” Participants considered current evidence for and against the hypothesis that AD could be caused or exacerbated by infection or commensal microbes. Discussion focused on connecting microglial transcriptional states to functional states, mouse models that better mimic human immunity, the potential involvement of inflammasome signaling, metabolic alterations, self-reactive T cells, gut microbes and fungal infections, and lessons learned from Covid-19 patients with neurologic symptoms. The content presented in the symposium, and major topics raised in discussions are reviewed in this summary of the proceedings.

Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remains unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We found that this peptide (ANXA1sp) inhibited postoperative NLRP3 inflammasome activation and prevented microglial activation in the hippocampus, reducing PND-like memory deficits. Together our results reveal a previously under-recognized role of hippocampal ANXA1 and NLRP3 inflammasome dysregulation in triggering postoperative neuroinflammation, offering a new target for advancing treatment of PNDs through the resolution of inflammation.

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here, we used multiple genetically modified mouse models to monitor activated inflammasomes in situ based on oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation during EAE was dependent on absent in melanoma 2 (AIM2), but low IL-1β release and no significant signs of cell death were found. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.