Retrospective cohort study identifying pulmonary complications in a cohort of patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi organ involvement. One of the most common manifestations is pulmonary disease with a reported prevalence between 5%-90%. PURPOSE: Given this wide range of prevalence, there is a need to more closely define types of pulmonary disease in SLE and associated risk factors. RESEARCH DESIGN: We sought to characterize the presentation of pulmonary manifestations in an established SLE cohort using electronic health record data. STUDY SAMPLE: All patients were >18 years of age and had confirmed SLE by a rheumatologist using SLICC or 2019 ACR/EULAR classification criteria. 220 patients with imaging were included in this study; average age was 42.5 years, 86.7% identified as female, 60.5% identified as white, 37.3% as Black, and 1.82% as Asian. ANALYSIS: Generalized estimating equations were utilized to analyze the data, accounting for its repeated measured nature. RESULTS: We found an association between smoking (present/prior smoker) and radiologist reported disease on computerized tomography (CT) scan, as well as an association between smoking (present/prior smoker), older age, and male sex with having pulmonary disease identified on chest X-ray. The most common findings on CT and X-ray were increased lung density (24%, 12%) and atelectasis (18%, 10%). The most common disease found on CT was pleural effusion (24%) and mediastinal/axillary lymphadenopathy (16%). CONCLUSION: While our study is limited by the retrospective nature, our results show that certain factors, namely smoking, older age, or male sex should prompt clinicians to have a higher suspicion for lung disease in SLE patients.

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries offer more nuanced and accurate insights into the regulatory mechanisms of RNA editing in the human brain.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

The value of additional electrodes when stereo-electroencephalography is inconclusive.

OBJECTIVE: Stereo-electroencephalography (SEEG) is the preferred method for intracranial localization of the seizure-onset zone (SOZ) in drug-resistant focal epilepsy. Occasionally SEEG evaluation fails to confirm the pre-implantation hypothesis. This leads to a decision tree regarding whether the addition of SEEG electrodes (two-step SEEG - 2sSEEG) or placement of subdural electrodes (SDEs) after SEEG (SEEG2SDE) would help. There is a dearth of literature encompassing this scenario, and here we aimed to characterize outcomes following unplanned two-step intracranial EEG (iEEG). METHODS: All 225 adult SEEG cases over 8 years at our institution were reviewed to extract patient data and outcomes following a two-step evaluation. Three raters independently quantified benefits of additional intracranial electrodes. The relationship between two-step iEEG benefit and clinical outcome was then analyzed. RESULTS: Fourteen patients underwent 2sSEEG and nine underwent SEEG2SDE. In the former cohort, the second SEEG procedure was performed for these reasons-precise localization of the SOZ (36%); defining margins of eloquent cortex (21%); and broadening coverage in the setting of non-localizable seizure onsets (43% of cases). Sixty-four percent of 2sSEEG cases were consistently deemed beneficial (Light's κ = 0.80). 2sSEEG performed for the first two indications was much more beneficial than when onsets were not localizable (100% vs 17%, p = .02). In the SEEG2SDE cohort, SDEs identified the SOZ and enabled delineation of margins relative to eloquent cortex in all cases. SIGNIFICANCE: The two-step iEEG is useful if the initial evaluation is broadly concordant with the original electroclinical hypothesis, where it can clarify onset zones or delineate safe surgical margins; however, it provides minimal benefit when the implantation hypothesis is erroneous, and we recommend that 2sSEEG not be generally utilized in such cases. SDE implantation after SEEG minimizes the need for SDEs and is helpful in delineating surgical boundaries relative to ictal-onset zones and eloquent cortex.

Developing a nutrition screening tool for children with cystic fibrosis ages 0 to 2 years: Children with cystic fibrosis nutrition screening tool.

BACKGROUND: For children with cystic fibrosis (CF), achieving and maintaining optimal growth by the age of 2 years is critical for future health outcomes. A standardized nutrition screening is needed to identify growth problems, enable timely interventions, and improve nutritional outcomes for children (0 to 2 years) with CF. The purpose of this study was to develop a nutrition screening tool for children (0 to 2 years) with CF to identify nutrition risk at every clinical encounter. METHODS: A retrospective cross-sectional study was used to develop a nutrition screening tool to determine if nutrition interventions needed to change (at-risk) or continue (not at-risk). Retrospective data for pertinent nutrition factors were collected for 99 children attending an accredited CF clinic. The nutrition factors were compared to a dietitian assessment. A stepwise discriminant analysis determined weight-for-age (WFA) and weight-for-length (WFL) z-scores were significant. Then anthropometric data and corresponding dietitian assessment results were collected for children with CF attending two other accredited CF clinics (n = 29, n = 30). Discriminant analysis was used to determine sensitivity and specificity of the nutrition factors and to create a nutrition screening tool equation. RESULTS: The nutrition screening model that included WFA z-score, LFA z-score, WFL z-score, and weight change velocity adequacy determined nutrition risk the best. The sensitivity was 89.7 %, specificity 83.2 %, NPV 93.3 %, and PPV 75.4 % for this model. CONCLUSION: The nutrition screening tool equation developed in this study standardizes the process to identify children (0 to 2 years) with CF at nutrition risk. Further validation is needed.

Lysine-specific demethylase 1 as a therapeutic cancer target: observations from preclinical study.

INTRODUCTION: Lysine-specific histone demethylase 1A (KDM1A/LSD1) has emerged as an important therapeutic target in various cancer types. LSD1 regulates a wide range of biological processes that influence cancer development, progression, metastasis, and therapy resistance. However, recent studies have revealed novel aspects of LSD1 biology, shedding light on its involvement in immunogenicity, antitumor immunity, and DNA damage response. These emerging findings have the potential to be leveraged in the design of effective LSD1-targeted therapies. AREAS COVERED: This paper discusses the latest developments in the field of LSD1 biology, focusing on its role in regulating immunogenicity, antitumor immunity, and DNA damage response mechanisms. The newfound understanding of these mechanisms has opened possibilities for the development of novel LSD1-targeted therapies for cancer treatment. Additionally, the paper provides an overview of LSD1 inhibitor-based combination therapies for the treatment of cancer. EXPERT OPINION: Exploiting LSD1 role in antitumor immunity and DNA damage response provides cues to not only understand the LSD1-resistant mechanisms but also rationally design new combination therapies that are more efficient and less toxic than monotherapy. The exploration of LSD1 biology and the development of LSD1-targeted therapies hold great promise for the future of cancer treatment.

Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.

Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERß) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it remain unknown if KDM1A interacts with ERß and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERß expression showed an inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERß isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERß, and its inhibition enhances ERß target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERß agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERß agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERß signaling and that genes altered by KDM1A-KO and ERß agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in OCa orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERß expression/functions, and its inhibition improves ERß mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERß agonist combination therapy is a promising strategy for OCa.

[99mTc]-labelled anti-Programmed Death-Ligand 1 single-domain antibody SPECT/CT: a novel imaging biomarker for myocardial PD-L1 expression.

BACKGROUND: Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT. METHODS: Thoracic [99mTc]NM-01 SPECT/CT was performed in lung cancer patients (n = 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LVmax:BP) and (RVmax:BP) were measured. LVmax was compared to background skeletal muscle (musclemax). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: Mean LVmax:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks (p = 0.42). Mean RVmax:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks (p = 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LVmax to musclemax 3.71 ± 0.77 vs 0.98 ± 0.20 (p < 0.001)) and at least twofold for the RV (LVmax to musclemax 2.49 ± 0.63 vs 0.98 ± 0.20 (p < 0.001)). There was excellent intra-rater reliability for LVmax:BP with ICC 0.99 (95% confidence interval 0.94-0.99, p < 0.001), mean bias -0.05 ± 0.14 (95% limits of agreement -0.32 to 0.21). There were no major adverse cardiovascular events or myocarditis during follow-up. CONCLUSION: This study is the first to report PD-L1 expression of the heart that can be quantified non-invasively without invasive myocardial biopsy, with high reliability and specificity. This technique can be applied to investigate myocardial PD-L1 expression in ICI-associated myocarditis and cardiomyopathies. Clinical trial registration PD-L1 Expression in Cancer (PECan) study (NCT04436406). https://clinicaltrials.gov/ct2/show/NCT04436406 June 18th, 2020.

Inter-rater and intra-rater agreement of [99mTc]-labelled NM-01, a single-domain programmed death-ligand 1 (PD-L1) antibody, using quantitative SPECT/CT in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors, including those against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), are routinely used to treat non-small cell lung cancer (NSCLC). PD-L1 is a validated prognostic and predictive immunohistochemical biomarker of anti-PD-1/PD-L1 therapy but displays temporospatial heterogeneity of expression. Non-invasive radiopharmaceutical techniques, including technetium-99m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT, have the potential to improve the predictive value of PD-L1 assessment. This study aims to determine the inter- and intra-rater agreement of the quantitative measurement of [99mTc]NM-01 SPECT/CT in NSCLC. METHODS: Participants (n = 14) with untreated advanced NSCLC underwent [99mTc]NM-01 SPECT/CT at baseline (n = 3) or at baseline plus 9-week follow-up (n = 11). [99mTc]NM-01 uptake (of primary lung, lymph node, thoracic and distant metastases, and healthy reference tissues) was measured using SUVmax and malignant lesion-to-blood pool ratios with Siemens xSPECT Broad Quantification software by three independent raters. Intraclass correlation coefficients (ICC) were calculated and Bland-Altman plot analysis performed to determine inter- and intra-rater agreement. RESULTS: There was excellent inter-rater agreement of manual freehand SUVmax scores of primary lung tumour (T; n = 25; ICC 1.00; 95% CI 0.99-1.00), individual lymph node metastases (LN; n = 56; ICC 0.97; 95% CI 0.95-0.98), thoracic metastases (ThMet; n = 9; ICC 0.94; 95% CI 0.83-0.99) and distant metastases (DisMet; n = 21; ICC 0.91; 95% CI 0.83-0.96). The inter-rater ICCs of tumour-to-blood pool (T:BP), LN:BP, ThMet:BP and DisMet:BP measures of [99mTc]NM-01 uptake also demonstrated good or excellent agreement. Manual freehand scoring of T, LN, ThMet, DisMet and their ratios using [99mTc]NM-01 SPECT/CT following a 28-day interval was consistent for all raters with good or excellent intra-rater agreement demonstrated (ICCs range 0.86-1.00). CONCLUSION: Quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC, using SUVmax of malignant primary or metastatic lesions and their ratios with healthy reference tissues, demonstrated good or excellent inter- and intra-rater agreement in this study. Further validation with ongoing and future larger cohort studies is now warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT04436406 (registered 18th June 2020; available at https://clinicaltrials.gov/ct2/show/NCT04436406 ) and NCT04992715 (registered 5th August 2021; available at https://clinicaltrials.gov/ct2/show/NCT04992715 ).

Leveraging base-pair mammalian constraint to understand genetic variation and human disease.

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

Reticulocalbin 3 Is a Novel Mediator of Glioblastoma Progression.

Glioblastoma is the most common malignant primary brain tumor. Molecular mechanisms underlying the pathobiology of glioblastoma are incompletely understood, emphasizing an unmet need for the identification of new therapeutic candidates. Reticulocalbin 3 (RCN3), an ER lumen-residing Ca2+ binding protein, plays an essential role in protein biosynthesis processes via the secretory pathway. Emerging studies demonstrated that RCN3 is a target for therapeutic intervention in various diseases. However, a knowledge gap exists about whether RCN3 plays a role in glioblastoma. Publicly available datasets suggest RCN3 is overexpressed in glioblastoma and portends poor survival rates. The knockdown or knockout of RCN3 using shRNA or CRISPR/Cas9 gRNA, respectively, significantly reduced proliferation, neurosphere formation, and self-renewal of GSCs. The RNA-seq studies showed downregulation of genes related to translation, ribosome, and cytokine signaling and upregulation of genes related to immune response, stem cell differentiation, and extracellular matrix (ECM) in RCN3 knockdown cells. Mechanistic studies using qRT-PCR showed decreased expression of ribosomal and increased expression of ER stress genes. Further, in silico analysis of glioblastoma patient datasets showed RCN3 expression correlated with the ribosome, ECM, and immune response pathway genes. Importantly, the knockdown of RCN3 using shRNA significantly enhanced the survival of tumor-bearing mice in orthotopic glioblastoma models. Our study suggests that RCN3 could be a potential target for the development of a therapeutic intervention in glioblastoma.

Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.

Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma.

BACKGROUND: Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs). METHODS: Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo. RESULTS: TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ-mediated DNA damage. A combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced the survival of tumor-bearing mice. CONCLUSIONS: Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.

Safety and efficacy of bihemispheric sampling via transmidline stereoelectroencephalography.

OBJECTIVE: Stereoelectroencephalography (SEEG) is designed to target distributed cortical networks responsible for electroclinical seizure syndrome and to enable localization of the site of seizure onset in patients with intractable epilepsy. When the preimplantation hypothesis invokes the bilateral mesial frontal lobes, sampling of several deep-seated cortical sites in both hemispheres is required. In this study, the authors have demonstrated the feasibility of sampling bihemispheric areas with intentional implantation of an SEEG electrode crossing the midline (SECM) for sampling the cortex on both sides of the interhemispheric fissure. METHODS: An analysis of 231 consecutive SEEG procedures over 8 years was used to identify instances of bihemispheric sampling by using the transmidline SEEG technique. RESULTS: The authors identified 53 SEEG cases, with a total of 126 electrodes that crossed the interhemispheric fissure; all were in the frontal lobes. Eighty-three electrodes targeted the cingulate gyrus (18 rostral, 43 anterior, and 22 middle), 31 targeted the posterior orbitofrontal region, 8 sampled the medial prefrontal cortex, and 4 targeted nodular heterotopia around the frontal horns. The ictal onset zone was localized to the frontal lobe in 16 cases. SECM isolated interictal and ictal activity in the contralateral hemisphere in 6 cases and independent bihemispheric seizure activity in 2 cases. No hemorrhagic or infectious complications were noted in any of these cases. CONCLUSIONS: Based on this extensive experience of bihemispheric sampling, the authors concluded that this technique is safe and effective. In this series, SECM showed contralateral interictal and/or ictal epileptiform activity in 8 (15%) cases, and 9 (16%) cases (with unilateral implantation) had sufficient data to discard contralateral involvement, contributing to support of the epileptogenic network. SECM may reduce the number of electrodes used to sample bilateral mesial frontal or orbitofrontal cortices, and such an approach may lower the risk of hemorrhage and costs.

Prevalence of iatrogenic CNS inflammation at a tertiary neuroimmunology clinic.

BACKGROUND: Various vaccines, tumor-necrosis-factor-alpha inhibitors (TNFAIs), immune-checkpoint inhibitors (ICIs), and other immunomodulators have been linked to inflammatory CNS events. The prevalence of iatrogenic events in the neuroimmunology clinic is unknown. OBJECTIVE: To evaluate the prevalence and clinical characteristics of iatrogenic CNS inflammation in a tertiary neuroimmunology clinic. METHODS: We analyzed 422 consecutive patients seen over five years at a tertiary neuroimmunology clinic who were systematically screened for exposure to vaccines, TNFAIs, ICIs, or other immunomodulators. In patients with suspected iatrogenic events, the Naranjo Adverse Drug Reaction Probability Scale was used to score the probability of iatrogenicity. RESULTS: In total, 27 potential iatrogenic events were observed, accounting for 6.4% of all new referrals. The average Naranjo score was 5.78 +/- 1.65 with 74% of the cases scored as probable and 26% scored as possible. The clinical phenotypes included MS relapses (37%); autoimmune encephalitis (30%); NMOSD attacks (15%); transverse myelitis (11%); optic neuritis (4%); and MOGAD attacks (4%). A monophasic course was observed in 44% of cases while 41% had a relapsing course. All patients stopped or interrupted treatment with the offending agent. In addition, 41% of the iatrogenic events were fully responsive to corticosteroids; 22% were partially responsive; and 15% resolved spontaneously. The most common potential triggers were vaccines (37%) followed by TNFAIs (33%) then ICIs (26%). A significantly higher number of probable iatrogenic events were observed among the ICI and vaccine groups compared to a higher number of possible events among the TNFAI group. The latter group also had a significantly longer interval since exposure. The ICI group was more likely to present with monophasic autoimmune encephalitis. CONCLUSION: Iatrogenic CNS inflammation is rare and typically involves steroid-responsive monophasic events. A subset of iatrogenic events can unmask or worsen relapsing disorders. The probability of iatrogenicity was higher in vaccine and ICI-related events compared to TNFAI-related events.

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist.

Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERß) exerts tumor suppressor functions in OCa. However, the status of ERß expression in OCSCs and the therapeutic utility of the ERß agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERß, particularly ERß isoform 1, is highly expressed in OCSCs and that ERß agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERß agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.

Characterization and Classification of Keratinized Odontogenic Cysts in 29 Dogs.

This retrospective case series presents a unique group of odontogenic cysts that are lined by heavily keratinized epithelium and contain laminated keratin. Keratinized odontogenic cyst (KOC) is proposed as appropriate terminology for the described lesions. The series evaluates cysts from 29 dogs, including clinical presentation, diagnostic imaging, and histopathology. All 29 lesions occurred in tooth bearing regions of the jaws; 21 were maxillary and 8 were mandibular. These keratinized odontogenic cysts were unilocular or multilocular, and some demonstrated considerable expansion resulting in bone destruction. In 13 of 29 cases, there was evidence of tooth displacement associated with the expansion of the KOC. The KOCs did not have a distinctive radiographic appearance. 48% of the cysts had a soft tissue defect through which the keratin contents could be visualized. Cyst contents ranged from hard mineralized keratin to fluid consistency with soft flecks of keratin. The pathoetiology of KOCs is unknown; however, the biological behavior is benign and thought to be slowly progressive despite potential for locally destructive growth. Recurrence is uncommon when cyst enucleation and debridement are aggressive or when solid cysts are excised en bloc.

3D-Printed Polypyrrole Microneedle Arrays for Electronically Controlled Transdural Drug Release.

After the spinal cord injury, inflammation and cytotoxicity cause further damage to neural cells. The progression of this secondary injury might be reduced by the administration of anti-inflammatory drugs. To allow the local delivery of such drugs while minimizing dural opening, we have created a polypyrrole (PPy)-coated microneedle array using a microscale three-dimensional (3D) printing technology that facilitates electronically controlled encapsulation and the transdural release of drugs. PPy microneedles demonstrated an electronically controlled release of steroid dexamethasone (Dexa) in a novel in vitro transdural model and in vivo. The biological activity of the device was then tested by the electronic release of Dexa into an in vitro model of neuroinflammation, using activated microglia. Following electrically activated Dexa release, inflammation was reduced, as demonstrated by a decrease in nitric oxide and proinflammatory cytokines Il-6 and MCP-1. These results demonstrate the feasibility of PPy-coated microneedles for the transdural delivery of anti-inflammatory drugs to the central nervous system.

Creating Crosswalks for Knee Outcomes After ACL Reconstruction Between the KOOS and the IKDC-SKF.

BACKGROUND: Anterior cruciate ligament (ACL) registries do not all use the same patient-reported outcome measures, limiting comparisons and preventing pooling of data for meta-analysis. Our objective was to create a statistical crosswalk to convert cohort and registry mean Knee Injury and Osteoarthritis Outcome Scores (KOOS) to International Knee Documentation Committee-Subjective Knee Form (IKDC-SKF) scores and vice versa to allow these comparisons. METHODS: Data from 3 ACL registries were pooled (n = 14,412) and were separated into a training data set (70% of the sample) or a validation data set (30% of the sample). The KOOS and the IKDC-SKF scores were available prior to the operation and at 1, 2, and 5 or 6 years postoperatively. We used equipercentile equating methods to create crosswalks in the training data set and examined accuracy in the validation data set as well as bootstrapping analyses to assess the impact of sample size on accuracy. RESULTS: Preliminary analyses suggested that crosswalks could be attempted: large correlations between scores on the 2 measures (r = 0.84 to 0.94), unidimensionality of scores, and subpopulation invariance were deemed sufficient. When comparing actual scores with crosswalked scores in the validation data set, negligible bias was observed at the group level; however, individual score deviations were variable. The crosswalks are successful for the group level only. CONCLUSIONS: Our crosswalks successfully convert between the KOOS and the IKDC-SKF scores to allow for a group-level comparison of registry and other cohort data. CLINICAL RELEVANCE: These crosswalks allow comparisons among different national ligament registries as well as other research cohorts and studies; they also allow data from different patient-reported outcome measures to be pooled for meta-analysis. These crosswalks have great potential to improve our understanding of recovery after ACL reconstruction and aid in our ongoing efforts to improve outcomes and patient satisfaction, as well as to allow the continued analysis of historical data.