Citations

Abstract Glioblastoma is the most common and lethal primary brain tumor in adults, with a median survival less than 15 months despite current standard of care. Oncolytic immunovirotherapies (OVs) have shown promise in early clinical trials. OVs are engineered to specifically target cancer cells, trigger autophagic programmed cell death, and release tumor antigens in the context of T-cell activating cytokines. Cellular communication network factor 1 (CCN1) is an extracellular matrix protein expressed in 70% of glioblastomas that has been shown to drastically reduce OV efficacy, particularly herpes simplex virus type 1 (HSV-1). Our objectives were to decode protein-protein interaction (PPI) networks activated by CCN1, identify critical nodes in resistance networks, and use this analysis to design OVs that overcome CCN1-mediated resistance. We used NetDecoder to elucidate phenotype-specific PPI subnetworks in LN229 human glioblastoma cells with tetracycline-inducible CCN1 expression. Publicly available microarray data on CCN1-induced and control samples established differentially expressed genes, which served as sources in our PPI network to derive prioritized context-specific subnetworks. We found that 11 source genes collaborate via 39 deep nodes to confer OV resistance to CCN1-expressing glioblastomas. Of these, a router (IKBKE) and a sink (YBX1) have been previously implicated in glioblastoma pathogenesis. We conclude that autophagy regulator HSP90AA1, a critical node, may be targeted to improve OV efficacy in CCN1-expressing glioblastomas. Furthermore, WebGestalt overrepresentation analysis of subnetwork nodes suggests that oncolytic adenovirus may be more effective than HSV-1 as a synthetic biology chassis.

Abstract Background Although perceived barriers to applying to dermatology have been researched among medical students, there remains a dearth of literature dedicated to understanding perceptions that medical students have of the field of dermatology and dermatologists. Methods A review of the literature in Embase, Pubmed, Scopus, Web of Science, and ScienceDirect were carried out to identify articles and abstracts between 2016 and 2021 relating to medical student perceptions of the field of dermatology. Peer-reviewed English studies measuring attitudes/level of interest in dermatology or other specialities, understanding of dermatologic topics, procedures, and/or scope of practice were included. Duplicate studies and conference abstracts were excluded. All publications were screened using the PRISMA-Sc guidelines. Findings were summarised and tabulated accordingly. Results A total of nine articles met inclusion criteria and eight are included in this review since one was not accessible online. Notable findings include non-US medical students perceiving dermatology as monotonous, stigmatized, unfamiliar, and difficult to access with a misunderstanding of the diversity and severity of the conditions dermatologists treat. No data on US medical student perceptions was found. Perceptions were found to be influential in career planning: medical students may reject specialities after exposure to negative comments on the field. Factors attracting students to dermatology include the appeal of being a dermatologist, media portrayal, and dermatologists' influence on patients' lives. Completion of dermatology-related activities improved medical student interest, comfort, and understanding of the field. Early dermatology exposure in US undergraduate premedical students led to heightened interest in the field, more confidence in ability to find dermatology mentors, and increased perception that dermatology serves the needs of underserved communities. Conclusions This review demonstrates the need to further investigate medical student perceptions of dermatology, particularly in the United States. Perceptions of medical specialities can impact medical student career choices. Understanding which misconceptions may be preventing students from exploring dermatology can inform efforts towards improving diversity, equity, and inclusion: translating to an equitable match and improving patient outcomes. Limitations include exclusion of articles published before 2016, geographic variability in studies, and limited data on evolving student perceptions over time.

BACKGROUND: Refractory perianal Crohn’s disease remains notoriously difficult to treat. We developed a novel technology using a commercially available bioabsorbable fistula plug to deliver autologous adipose-derived mesenchymal stem cells. OBJECTIVE: This study aimed to assess therapeutic safety and feasibility in the completed STOMP (stem cells on matrix plugs) phase 1 clinical trial. DESIGN: Prospective single-arm phase I clinical trial. SETTING: Tertiary academic medical center. PATIENTS: Adults (aged 18–65 y) with complex single-tract Crohn’s disease perianal fistula who have failed conventional therapy were included in this study. INTERVENTION: Autologous adipose-derived mesenchymal stem cells were isolated, ex vivo culture expanded, and seeded onto a commercially available bioabsorbable fistula plug. Six weeks later, patients returned to the operating room for removal of the seton and placement of the stem cell-loaded plug. MAIN OUTCOME MEASURES: Patients were followed up for a total of 8 visits through 12 months. Safety was the primary end point; clinical healing and MRI response were secondary end points. RESULTS: Twenty patients (12 females; mean age 36 y) were treated with the stem cell–loaded plug. Of the 20 patients enrolled, 3 were not included in the 12-month analysis because of study withdrawal. Through 12 months, no patient experienced a serious adverse event related to the stem cell–loaded plug. Four patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events. Complete clinical healing occurred in 14 of 18 patients at 6 months and 13 of 17 patients at 12 months. MRI response was observed in 12 of 18 patients at 6 months. LIMITATIONS: The main limitations were the small sample size and restrictive inclusion criteria. CONCLUSIONS: A stem cell–loaded plug can safely and effectively deliver cell-based therapy for patients with single-tract fistulizing perianal Crohn’s disease. See Video Abstract at http://links.lww.com/DCR/C70. RESPUESTA DURADERA OBSERVADA EN PACIENTES CON ENFERMEDAD DE CROHN PERIANAL FISTULIZANTE REFRACTARIA MEDIANTE EL USO DE CÉLULAS MADRE MESENQUIMALES AUTÓLOGAS EN UNA MATRIZ DISOLUBLE: RESULTADOS DEL ENSAYO DE FASE I STEM CELL ON MATRIX PLUG ANTECEDENTES: La enfermedad de Crohn perianal refractaria sigue siendo notoriamente difícil de tratar. Desarrollamos una tecnología novedosa utilizando un tapón de fístula bioabsorbible disponible comercialmente para administrar células madre mesenquimales derivadas de tejido adiposo autólogo. OBJETIVO: Evaluar la seguridad y viabilidad terapéutica en el ensayo finalizado STOMP. DISEÑO: Ensayo clínico prospectivo de fase I de un solo brazo. AJUSTE: Centro médico académico terciario. PACIENTES: Adultos (18-65) con fístula perianal compleja de la enfermedad de Crohn de un solo tracto que han fracasado con la terapia convencional. INTERVENCIÓN: Se aislaron células madre mesenquimales derivadas de tejido adiposo autólogo, se expandieron en cultivo ex vivo y se sembraron en un tapón de fístula bioabsorbible disponible comercialmente. Seis semanas después, los pacientes regresaron al quirófano para retirar el setón y colocar el tapón cargado de células madre. PRINCIPALES MEDIDAS DE RESULTADO: Los pacientes fueron seguidos durante un total de 8 visitas durante 12 meses. La seguridad fue el criterio principal de valoración; la curación clínica y la respuesta a la resonancia magnética fueron criterios de valoración secundarios. RESULTADOS: Veinte pacientes (12 mujeres, edad media 36 años) fueron tratados con el tapón cargado de células madre. De los 20 pacientes inscritos, tres no se incluyeron en el análisis de 12 meses porque se retiraron del estudio. A lo largo de 12 meses, ningún paciente experimentó un evento adverso grave relacionado con el tapón cargado de células madre. Cuatro pacientes experimentaron 7 eventos adversos graves y 12 pacientes experimentaron 22 eventos adversos. La curación clínica completa ocurrió en 14 de 18 pacientes a los 6 meses y en 13 de 17 pacientes a los 12 meses. La respuesta a la resonancia magnética se observó en 12 de 18 pacientes a los 6 meses. LIMITACIONES: Las principales limitaciones son el tamaño pequeño de la muestra y los criterios de inclusión restrictivos. CONCLUSIONES: Un tapón cargado de células madre se puede administrar de manera segura y efectiva, una terapia basada en células para pacientes con enfermedad de Crohn perianal fistulizante de un solo tracto. Consule Video Resumen en http://links.lww.com/DCR/C70. (Traducción— Dr. Yesenia Rojas-Khalil)

Hexanucleotide G 4 C 2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G 4 C 2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72 450 mice. However, chronic administration of anti-GA antibodies in AAV-(G 4 C 2 ) 149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G 4 C 2 ) exp , causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G 4 C 2 ) exp and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G 4 C 2 ) exp and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo.

Currently available bioinformatics tools to identify BGCs from metagenomic sequencing data are limited in their predictive capability or ease of use to even computationally oriented researchers. We present an automated computational pipeline called TaxiBGC, which predicts experimentally characterized BGCs (and infers their known SMs) in shotgun metagenomes by first considering the microbial species source.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N‐Methyl‐D‐aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high‐dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297–302