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BackgroundThe effectiveness of somatic neoantigen-based immunotherapy is often hindered by the limited number of mutations in tumors with low to moderate mutation burden. Focusing on microsatellite-stable colorectal cancer (CRC), this study investigates the potential of tumor-associated circular RNAs (circRNAs) as an alternative source of neoepitopes in CRC.MethodsTumor-associated circRNAs in CRC were identified using the MiOncoCirc database and ribo-depletion RNA sequencing of paired clinical normal and tumor samples. Candidate circRNA expression was validated by quantitative real-time PCR (RT-qPCR) using divergent primers. TransCirc database was used for translation prediction. Human leukocyte antigen binding affinity of open reading frames from potentially translatable circRNA was predicted using pVACtools. Strong binders from messenger RNA-encoded proteins were excluded using BlastP. The immunogenicity of the candidate antigens was functionally validated through stimulation of naïve CD8+ T cells against the predicted neoepitopes and subsequent analysis of the T cells through enzyme-linked immunospot (ELISpot) assay, intracellular cytokine staining (ICS) and granzyme B (GZMB) reporter. The cytotoxicity of T cells trained with antigen peptides was further tested using patient-derived organoids.ResultsWe identified a neoepitope from circRAPGEF5 that is upregulated in CRC tumor samples from MiOncoCirc database, and two neoepitopes from circMYH9, which is upregulated across various tumor samples from our matched clinical samples. The translation potential of candidate peptides was supported by Clinical Proteomic Tumor Analysis Consortium database using PepQuery. The candidate peptides elicited antigen-specific T cells response and expansion, evidenced by various assays including ELISpot, ICS and GZMB reporter. Furthermore, T cells trained with circMYH9 peptides were able to specifically target and eliminate tumor-derived organoids but not match normal organoids. This observation underscores the potential of circRNAs as a source of immunogenic neoantigens. Lastly, circMYH9 was enriched in the liquid biopsies of patients with CRC, thus enabling a detection-to-vaccination treatment strategy for patients with CRC.ConclusionsOur findings underscore the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels.

Intron retention (IR) is an underexplored source of alternative neoantigens in cancer. Unlike mutation-derived neoantigens, IR-derived neoantigens can arise even in malignancies with low tumour mutational burden (TMB), such as microsatellite-stable colorectal cancer (MSS-CRC), making them a potentially important source of tumour antigens. Here, we provide experimental evidence that IR-derived neoantigens are expressed in tumours and are recognized by T cells, with approximately 30% of predicted epitopes eliciting measurable CD8 + T cell responses. We applied a bioinformatics pipeline to RNA sequencing data from 23 CRC patients, identifying 49 patient-specific and 24 shared IR-derived neoantigens, the latter present in ~ 30% of the cohort. Notably, most shared neoantigens exhibited high binding affinity to the predominant HLA alleles, highlighting their potential as broadly targetable vaccine candidates. Together, these findings establish IR-derived neoantigens as a validated and clinically relevant class of tumour antigens, expanding opportunities for personalized and off-the-shelf immunotherapies in CRC and other low-TMB cancers.

Hashimoto’s encephalopathy (HE) is a rare diagnosis with a heterogenous presentation. It may not be directly related to thyroid dysfunction as most patients are euthyroid when the symptoms start. There has been a lack of consensus building on the pathophysiology of HE, but most of the evidence points towards autoimmune vasculitis as the underlying process. HE can present as seizures, cognitive dysfunction, tremors, or stroke-like symptoms with focal neurological deficits. Cerebellar ataxia (motor incoordination due to dysfunction of the cerebellum) is seen in HE but is a rare occurrence.The objective of the article was to present a case of cerebellar ataxia in a patient with Hashimoto’s thyroiditis. A 30-year-old previously healthy female presented with quickly progressive cerebellar ataxia, bilateral (B/L) limb weakness, and excessive tearing. She was found to have high titers of anti-TPO (anti-thyroid peroxidase) antibodies; a biopsy confirmed Hashimoto’s thyroiditis and a battery of negative tests excluding other causes of encephalopathy. Hence, confirming a diagnosis of HE. The patient was given glucocorticoids which relieved her symptoms. After being symptom-free for a few months, she relapsed and was unsuccessfully treated by the steroids. Upon this, she was given IV immunoglobulins, which helped achieve complete resolution. HE can be treated with immunotherapy, and most patients have a good prognosis, but some can have persistent neurological defects if left untreated or treatment is delayed. Relapses are common and may require a more extended treatment regimen.

Background and purposeCerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs.MethodsIn this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs.ResultsA total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH.ConclusionsIn Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins.

We present an implementation of the trimmed serendipity finite element family, using the open source finite element package Firedrake. The new elements can be used seamlessly within the software suite for problems requiring \\(H^1\\), or -conforming elements on meshes of squares or cubes. To test how well trimmed serendipity elements perform in comparison to traditional tensor product elements, we perform a sequence of numerical experiments including the primal Poisson, mixed Poisson, and Maxwell cavity eigenvalue problems. Overall, we find that the trimmed serendipity elements converge, as expected, at the same rate as the respective tensor product elements while being able to offer significant savings in the time or memory required to solve certain problems.

Background Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions. Methods We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis. Results Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS. Conclusions These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL 1 gene harbors a copy of the human endogenous retrovirus HML-2 , whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology. Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Warfarin sensitivity has been reported to be associated with increased incidence of international normalized ratio (INR) > 5. However, whether warfarin sensitivity is a risk factor for adverse outcomes in critically ill patients remains unknown. In the present study, we aimed to evaluate the utility of different machine learning algorithms for the prediction of warfarin sensitivity and to determine the impact of warfarin sensitivity on outcomes in critically ill patients. Nine different machine learning algorithms for the prediction of warfarin sensitivity were tested in the International Warfarin Pharmacogenetic Consortium cohort and Easton cohort. Furthermore, a total of 7,647 critically ill patients was analyzed for warfarin sensitivity on in-hospital mortality by multivariable regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. We found that logistic regression (AUC = 0.879, 95% CI: 0.834-0.924) was indistinguishable from support vector machine with a linear kernel, neural network, AdaBoost and light gradient boosting trees, and significantly outperformed all the other machine learning algorithms. Furthermore, we found that warfarin sensitivity predicted by the logistic regression model was significantly associated with worse in-hospital mortality in critically ill patients with an odds ratio (OR) of 1.33 (95% CI, 1.01-1.77). Our data suggest that the logistic regression model is the best model for the prediction of warfarin sensitivity clinically and that warfarin sensitivity is likely to be a risk factor for adverse outcomes in critically ill patients.

Background and Aims: Both non-alcoholic fatty liver disease (NAFLD) and depression have a high global prevalence which is projected to increase further. While studies exploring the association have been done, there are conflicting data. This study aims to assess the prevalence and association between depression and NAFLD. Methods: Medline and Embase were searched from inception to March 3, 2020. Meta-analysis of proportions using the generalized linear mix model was conducted to analyze the pooled prevalence of depression in NAFLD patients. Risk factors for depression in NAFLD patients were evaluated in conventional pairwise meta-analysis. Results: Ten studies involving 2,041,752 NAFLD patients were included. Pooled prevalence of depression was 18.21% (CI: 11.12–28.38%) in patients with NAFLD and 40.68% (CI: 25.11–58.37%) in patients with non-alcoholic steatohepatitis (NASH). NAFLD resulted in significantly higher risk of development of depression (OR: 1.29, CI: 1.02–1.64, p = 0.03). NASH patients had a significantly higher risk of depression compared with NAFLD patients (RR: 2.83, CI: 2.41–3.32, p < 0.001). Diabetes, body mass index (BMI), female sex, smoking, and history of pulmonary disease were significant risk factors for depression in NAFLD patients. Conclusion: This study demonstrated a high prevalence of depression in NAFLD patients and a significant association between both conditions. Furthermore, patients with NASH had a significantly higher risk of depression compared with those with NAFLD. Diabetes, BMI, history of lung disease or smoking, and female gender were significant risk factors. Further studies investigating the pathophysiological mechanism underlying depression and NAFLD are needed.

Introduction Sotrovimab, a recombinant human monoclonal antibody (mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had US Food and Drug Administration Emergency Use Authorization for the treatment of high-risk outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19) from 26 May 2021 to 5 April 2022. Real-world clinical effectiveness of sotrovimab in reducing the risk of 30-day all-cause hospitalization and/or mortality was evaluated for the period when the prevalence of circulating SARS-CoV-2 variants changed between Delta and Omicron in the USA. Methods A retrospective analysis was conducted of de-identified patients diagnosed with COVID-19 between 1 September 2021 to 30 April 2022 in the FAIR Health National Private Insurance Claims database. Patients meeting high-risk criteria were divided into two cohorts: sotrovimab and not treated with a mAb (“no mAb”). All-cause hospitalizations and facility-reported mortality ≤ 30 days of diagnosis (“30-day hospitalization or mortality”) were identified. Multivariable and propensity score-matched Poisson and logistic regressions were conducted to estimate the adjusted relative risk (RR) and odds of 30-day hospitalization or mortality in each cohort. Results Compared with the no mAb cohort ( n  = 1,514,868), the sotrovimab cohort ( n  = 15,633) was older and had a higher proportion of patients with high-risk conditions. In the no mAb cohort, 84,307 (5.57%) patients were hospitalized and 8167 (0.54%) deaths were identified, while in the sotrovimab cohort, 418 (2.67%) patients were hospitalized and 13 (0.08%) deaths were identified. After adjusting for potential confounders, the sotrovimab cohort had a 55% lower risk of 30-day hospitalization or mortality (RR 0.45, 95% CI 0.41–0.49) and an 85% lower risk of 30-day mortality (RR 0.15, 95% CI 0.08–0.29). Monthly, from September 2021 to April 2022, the RR reduction for 30-day hospitalization or mortality in the sotrovimab cohort was maintained, ranging from 46% to 71% compared with the no mAb cohort; the RR estimate in April 2022 was uncertain, with wide confidence intervals due to the small sample size. Conclusion Sotrovimab was associated with reduced risk of 30-day all-cause hospitalization and mortality versus no mAb treatment. Clinical effectiveness persisted during Delta and early Omicron variant waves and among all high-risk subgroups assessed.