Downregulation of hsa-miR-132 and hsa-miR-129: non-coding RNA molecular signatures of Alzheimer's disease.

Alzheimer's disease (AD) affects the elderly population by causing memory impairments, cognitive and behavioral abnormalities. Currently, no curative treatments exist, emphasizing the need to explore therapeutic options that modify the progression of the disease. MicroRNAs (miRNAs), as non-coding RNAs, demonstrate multifaceted targeting potential and are known to be dysregulated in AD pathology. This mini review focuses on two promising miRNAs, hsa-miR-132 and hsa-miR-129, which consistently exhibit differential regulation in AD. By employing computational predictions and referencing published RNA sequencing dataset, we elucidate the intricate miRNA-mRNA target relationships associated with hsa-miR-132 and hsa-miR-129. Our review consistently identifies the downregulation of hsa-miR-132 and hsa-miR-129 in AD brains as a non-coding RNA molecular signature across studies conducted over the past 15 years in AD research.

Peroxiredoxin 1 inhibits streptozotocin-induced Alzheimer's disease-like pathology in hippocampal neuronal cells via the blocking of Ca2+/Calpain/Cdk5-mediated mitochondrial fragmentation.

Oxidative stress plays an essential role in the progression of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer's disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we evaluated whether Peroxiredoxin 1 (Prx1) affects STZ-induced AD-like pathology and cellular toxicity. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed the STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting against oxidative stress.

Youth attention, perceptions, and appeal in response to e-cigarette advertising features: A focus group study.

Background: E-cigarette marketing exposure may influence vaping-related outcomes among youth, but less is known on which specific advertising features impact youth attention, perceptions, and appeal. This study qualitatively examines responses to different e-cigarette advertising features among e-cigarette-naïve youth. Methods: We conducted four online focus groups in 2021 with a national U.S. sample of 13-17 year olds (n = 25) who had never used e-cigarettes. Participants viewed and discussed their reactions to different e-cigarette advertisements varying in the inclusion of ad features, including color, models in imagery, text claims targeting smokers, and the nicotine warning label. Results: Participants were attracted to ads with bright colors, particularly when contrasted against a dark background. Ads featuring models attracted attention and reduced perceptions that the product is harmful. Comments indicated mixed reactions to smoker-targeted text claims. On one hand, participants perceived ads with text that specified "for smokers" as targeting older adults. On the other hand, text referring to "switching" from cigarettes to e-cigarettes led to some perceptions that the product is healthy, and certain text that implicitly referred to smoking (e.g., "no odor") had the potential to appeal to youth who wanted to use e-cigarettes discreetly. The level of attention paid to warnings depended on warning size and the color contrast between the warning and the rest of the ad. Conclusions: Findings suggest specific e-cigarette ad features play an important role in attracting youth attention and influencing perceptions. More research is needed on the potential public health benefits versus unintended consequences of smoker-targeted text claims.

EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond.

Delineation of the role of G6PD in Alzheimer's disease and potential enhancement through microfluidic and nanoparticle approaches.

Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aß deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.

Neuroprotective potential of Betulinic acid against TIO2NP induced neurotoxicity in zebrafish.

Betulinic acid (BA) is a natural triterpenoid extracted from Bacopa monnieri. BA has been reported to be used as a neuroprotective agent, but their molecular mechanisms are still unknown. Therefore, in this study, we attempted to investigate the precise mechanism of BA for its protective effect against Titanium dioxide nanoparticles (TiO2NP) induced neurotoxicity in zebrafish. Hence, our study observation showed that 10 µg/ml dose of TiO2NP caused a rigorous behavioral deficit in zebrafish. Further, biochemical analysis revealed TiO2NP significantly decreased GSH, and SOD, and increased MDA, AChE, TNF-α, IL-1ß, and IL-6 levels, suggesting it triggers oxidative stress and neuroinflammation. However, BA at doses of 2.5,5,10 mg/kg improved behavioral as well as biochemical changes in zebrafish brain. Moreover, BA also significantly raised the levels of DA, NE, 5-HT, and GABA and decreased glutamate levels in TiO2NP-treated zebrafish brain. Our histopathological analysis proved that TiO2NP causes morphological changes in the brain. These changes were expressed by increasing pyknotic neurons, which were dose-dependently reduced by Betulinic acid. Likewise, BA upregulated the levels of NRF-2 and HO-1, which can reduce oxidative stress and neuroinflammation. Thus, our study provides evidence for the molecular mechanism behind the neuroprotective effect of Betulinic acid. Rendering to the findings, we can consider BA as a suitable applicant for the treatment of AD-like symptoms.

Disease burden, clinical management and unmet treatment need of patients with moderate to severe atopic dermatitis; consensus statements, insights and practices from CERTADE (Central/Eastern EU, Russia, Turkiye AD Experts) Delphi panel.

Background: There is limited insight into the current disease burden and everyday clinical management of moderate-to- severe AD in Poland, Czechia, Russia, and Turkiye. Therefore, this study aimed to get information-driven insights regarding the current disease burden and clinical management of patients with moderate-to-severe AD with common and differentiating aspects of the patient journey and establish a consensus. Methods: In this modified 2-round Delphi panel, 133 questions were asked in total to 27 dermatologists. A consensus was achieved when 70% of the panel members strongly agreed or agreed (or strongly disagreed or disagreed) with an item. Statements with <40% agreement dropped from the Delphi rounds and were not repeated. Results: The results state that AD has a significant impact on the quality of life for both patients and their families with social and economic consequences in these countries. While there were significant dissimilarities regarding the current treatment approach by preference order and treatment duration among participants, there was also a high percentage of consensus on literature and guideline-based statements. Current topical therapies and the immune response modifiers were not found to be sufficient by panelists to cover the therapeutic needs of patients with moderate-to-severe AD. Moreover, panelists highlighted the significant burden of adverse events with the off-label use of currently available immunosuppressants. Conclusions: These results underlined that there is a significant disease burden with an unmet treatment need for patients with moderate-to-severe AD in Poland, Czechia, Russia, and Turkiye.

Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs.

Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced in vitro models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the in vitro discovery of targets and therapies against NDDs.

Generative AI unlocks PET insights: brain amyloid dynamics and quantification.

Introduction: Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography (PET) imaging plays a pivotal role because it allows for the visualization and quantification of abnormal amyloid beta (Aß) load in the living brain, providing a powerful tool for tracking disease progression and evaluating the efficacy of anti-amyloid therapies. Generative artificial intelligence (AI) can learn complex data distributions and generate realistic synthetic images. In this study, we demonstrate for the first time the potential of Generative Adversarial Networks (GANs) to build a low-dimensional representation space that effectively describes brain amyloid load and its dynamics. Methods: Using a cohort of 1,259 subjects with AV45 PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we develop a 3D GAN model to project images into a latent representation space and generate back synthetic images. Then, we build a progression model on the representation space based on non-parametric ordinary differential equations to study brain amyloid evolution. Results: We found that global SUVR can be accurately predicted with a linear regression model only from the latent representation space (RMSE = 0.08 ± 0.01). We generated synthetic PET trajectories and illustrated predicted Aß change in four years compared with actual progression. Discussion: Generative AI can generate rich representations for statistical prediction and progression modeling and simulate evolution in synthetic patients, providing an invaluable tool for understanding AD, assisting in diagnosis, and designing clinical trials. The aim of this study was to illustrate the huge potential that generative AI has in brain amyloid imaging and to encourage its advancement by providing use cases and ideas for future research tracks.

Repetitive Transcranial Magnetic Stimulation Improves Hippocampal N-Acetlaspartate Levels and Visual Memory Scores in Alzheimer's Disease.

The latest research into the pathophysiology of Alzheimer's Disease (AD) has included several cognitive deficits related to hippocampal functioning. However, current clinical research fails to consider the full extent of the heterogeneous cognitive spectrum of AD, resulting in a lack of the specific methods required to draw definitive diagnostic and therapeutic conclusions. This also includes in-vivo metabolic measurements for tailoring the diagnostic and therapeutic regimens in humans with AD. Magnetic resonance spectroscopy and repetitive transcranial magnetic stimulation (rTMS) are two novel diagnostic and therapeutic approaches that must be modified to treat AD. In the present study, we aimed to investigate the underlying therapeutic role of rTMS in humans with AD by evaluating the in-vivo hippocampal metabolites before and after rTMS treatment. Based on the data obtained using the fMRI data in our previous study and on the references reported in the literature, in the present study, we decided to use hippocampal NAA data after rTMS stimulation and found a significant increase in NAA levels. To the best of our knowledge, no other study has evaluated the effect of rTMS on hippocampal metabolites in humans with AD.

CT findings, prognosis, and follow-up of pulmonary artery periadventitial hematoma with aortic dissection: a retrospective single-center study.

Background: Pulmonary artery periadventitial hematoma (PAPH) with aortic dissection (AD) is a rare condition but has been reported to correlate with prognosis. However, there are few cases of PAPH, and the relationship with computed tomography (CT) findings of AD are unknown. This study aimed to evaluate CT findings and early prognosis in patients with PAPH in AD. Methods: This was a retrospective analysis of data from patients with Stanford type A AD diagnosed with contrast-enhanced CT in our institution from April 2008 to February 2023; 316 patients were included in the analyses. Patients comprised a PAPH group (n=78) and a non-PAPH group (n=238). The PAPH group was further divided into a group that died within 1 week of onset (death group; n=15) and a group that survived (alive group; n=63). PAPH was classified into three grades on the basis of the CT findings, as follows: Grade 1: PAPH only in the mediastinum; Grade 2: PAPH that extended into the lung field, with/without interlobular septa; and Grade 3: PAPH with pulmonary hemorrhage. Results: Compared with the non-PAPH group, the PAPH group had higher rates of early death (P=0.001), pericardial (P<0.001) and mediastinal hemorrhage (P<0.001). When comparing the death and alive groups, there was a significant difference in the rates of inoperable case (P<0.001), Grade 3 PAPH (PAPH with pulmonary hemorrhage) (P<0.001), and hemothorax (P=0.02). Multivariable analysis showed a significant association between Grade 3 PAPH (PAPH with pulmonary hemorrhage) and early death (P=0.004). Conclusions: Standard type A AD with PAPH is not rare. Mortality was higher in the PAPH group vs. the non-PAPH group, and Grade 3 PAPH (PAPH with pulmonary hemorrhage) was a significant risk factor for early death.

Low-dose ondansetron: A candidate prospective precision medicine to treat alcohol use disorder endophenotypes.

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. METHODS: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. RESULTS: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. CONCLUSIONS: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease.

Electroencephalogram (EEG) studies have suggested compensatory brain overactivation in cognitively healthy (CH) older adults with pathological beta-amyloid(Aß42)/tau ratios during working memory and interference processing. However, the association between glutamatergic metabolites and brain activation proxied by EEG signals has not been thoroughly investigated. We aim to determine the involvement of these metabolites in EEG signaling. We focused on CH older adults classified under (1) normal CSF Aß42/tau ratios (CH-NATs) and (2) pathological Aß42/tau ratios (CH-PATs). We measured plasma glutamine, glutamate, pyroglutamate, and γ-aminobutyric acid concentrations using tandem mass spectrometry and conducted a correlational analysis with alpha frequency event-related desynchronization (ERD). Under the N-back working memory paradigm, CH-NATs presented negative correlations (r = ~-0.74--0.96, p = 0.0001-0.0414) between pyroglutamate and alpha ERD but positive correlations (r = ~0.82-0.95, p = 0.0003-0.0119) between glutamine and alpha ERD. Under Stroop interference testing, CH-NATs generated negative correlations between glutamine and left temporal alpha ERD (r = -0.96, p = 0.037 and r = -0.97, p = 0.027). Our study demonstrated that glutamine and pyroglutamate levels were associated with EEG activity only in CH-NATs. These results suggest cognitively healthy adults with amyloid/tau pathology experience subtle metabolic dysfunction that may influence EEG signaling during cognitive challenge. A longitudinal follow-up study with a larger sample size is needed to validate these pilot studies.

Combining the AD8 and MMSE for community-based dementia screening.

BACKGROUND: This study aimed to determine whether a cognitive test the Mini-Mental State Examination (MMSE) and the Ascertain Dementia 8 (AD8) instrument applied in combination could improve the accuracy of dementia detection in a community setting. METHODS: Study participants were recruited from a community-based integrated screening program in Tainan, Taiwan. Participants completed the AD8 and were administered the Chinese version of the MMSE by psychologists. In addition, the presence of dementia was determined by neurologists based on the 2011 National Institute on Aging-Alzheimer's Association guidelines. Logistic regression analysis determined whether the combination of these two tests provided any additional information for dementia detection than either test alone. Receiver operating characteristic (ROC) curve analyses were conducted to explore the performances of different screening modalities in detecting dementia. RESULT: In total, 282 participants with an average age of 69.31 ± 10.27 years were enrolled. The prevalence of dementia among participants aged ≥65 years was 9.29 %. The sensitivity and specificity of the AD8 applied alone for detecting dementia were 64.71 % and 87.89 %, respectively, and of the MMSE applied alone, after adjusting for education level, were 41.18 % and 84.50 %, respectively. Using a cutoff score of 21 for the MMSE resulted in sensitivity of 77.78 % and specificity of 73.58 %. The AD8 and MMSE when combined in parallel yielded 88.89 % sensitivity and 70.16 % specificity. The serial use of the AD8 followed by the MMSE yielded 50 % sensitivity and 93.02 % specificity. Except for when an MMSE cutoff value of 26 was applied, the sensitivity of all examined modalities was poor and specificity was moderate for detecting mild cognitive impairment. ROC curve analysis revealed that the parallel application of the MMSE and AD8 (area under the ROC curve [AUC]: 82.3 % [75.1 %-89.4 %]) resulted in better dementia detection accuracy than the AD8 alone (AUC: 73.3 % [60.7 %-85.9 %]), the MMSE alone (AUC: 77.4 % [67.6 %-87.3 %]), or serial test administration (AUC: 67.6 % [53.4 %-81.8 %]). CONCLUSION: This study successfully demonstrated that the MMSE and AD8 combination for dementia screening could improve detection accuracy in a community setting.

A Simple Sandwich Electrochemical Immunosensor for Rapid Detection of the Alzheimer's Disease Biomarker Tau Protein.

As a typical biomarker of Alzheimer's disease, rapid and specific detection of tau protein can help improve the early diagnosis and prognosis of the disease. In this study, a simple sandwich electrochemical immunosensor was developed for rapid detection of tau protein. Primary monoclonal antibodies (mAb1) against the middle domain of tau protein (amino acids 189-195) were immobilized on the gold electrode surface through a self-assembled monolayer (SAM) of 3,3'-dithiobis (sulfosuccinimidyl propionate) (DTSSP). Then the tau protein was captured through the specific adsorption between the antigen and the antibody, resulting in a change in the impedance. Secondary monoclonal antibodies (mAb2) against the N-terminal region of tau protein were used for further amplification of the binding reaction between mAb1 and tau protein. A linear correlation between the total change in impedance and the logarithm of tau concentration was found from 2 × 10-6 mg mL-1 to 2 × 10-3 mg mL-1, with a detection limit as low as 1 × 10-6 mg mL-1. No significant interference was observed from human serum albumin. Furthermore, the fabricated sandwich immunosensor successfully detected target tau protein in artificial cerebrospinal fluid (aCSF) samples, indicating good potential for clinical applications in the future.

The Rare Adverse Effect of Myalgia After Dupilumab Biologic Therapy for Refractory Atopic Dermatitis.

Dupilumab, a systemic injectable biologic, can be prescribed to patients with atopic dermatitis who do not respond to topical treatments. Atopy can frequently subside by blocking inflammatory pathways, such as interleukin-4 (IL-4) and interleukin-13 (IL-13) in the immune system. Dupilumab is generally well-tolerated and mild; the most common adverse reactions listed are arthralgia, back pain, and conjunctivitis, which clears upon cessation or finalization of dupilumab therapy. This case report describes a patient experiencing severe myalgia - a rare adverse effect. The patient's atopic dermatitis was refractory toward topical treatments, but within one month of starting dupilumab, he experienced severe myalgias and muscle spasms, which prompted cessation of dupilumab despite it working well for his atopic dermatitis.

A feature-aware multimodal framework with auto-fusion for Alzheimer's disease diagnosis.

Alzheimer's disease (AD), one of the most common dementias, has about 4.6 million new cases yearly worldwide. Due to the significant amount of suspected AD patients, early screening for the disease has become particularly important. There are diversified types of AD diagnosis data, such as cognitive tests, images, and risk factors, many prior investigations have primarily concentrated on integrating only high-dimensional features and simple fusion concatenation, resulting in less-than-optimal outcomes for AD diagnosis. Therefore, We propose an enhanced multimodal AD diagnostic framework comprising a feature-aware module and an automatic model fusion strategy (AMFS). To preserve the correlation and significance features within a low-dimensional space, the feature-aware module employs a low-dimensional SHapley Additive exPlanation (SHAP) boosting feature selection as the initial step, following this analysis, diverse tiers of low-dimensional features are extracted from patients' biological data. Besides, in the high-dimensional stage, the feature-aware module integrates cross-modal attention mechanisms to capture subtle relationships among different cognitive domains, neuroimaging modalities, and risk factors. Subsequently, we integrate the aforementioned feature-aware module with graph convolutional networks (GCN) to address heterogeneous data in multimodal AD, while also possessing the capability to perceive relationships between different modalities. Lastly, our proposed AMFS autonomously learns optimal parameters for aligning two sub-models. The validation tests using two ADNI datasets show the high accuracies of 95.9% and 91.9% respectively, in AD diagnosis. The methods efficiently select features from multimodal AD data, optimizing model fusion for potential clinical assistance in diagnostics.

A spatiotemporal graph transformer approach for Alzheimer's disease diagnosis with rs-fMRI.

Alzheimer's disease (AD) is a neurodegenerative disease accompanied by cognitive impairment. Early diagnosis is crucial for the timely treatment and intervention of AD. Resting-state functional magnetic resonance imaging (rs-fMRI) records the temporal dynamics and spatial dependency in the brain, which have been utilized for automatically diagnosis of AD in the community. Existing approaches of AD diagnosis using rs-fMRI only assess functional connectivity, ignoring the spatiotemporal dependency mining of rs-fMRI. In addition, it is difficult to increase diagnosis accuracy due to the shortage of rs-fMRI sample and the poor anti-noise ability of model. To deal with these problems, this paper proposes a novel approach for the automatic diagnosis of AD, namely spatiotemporal graph transformer network (STGTN). The proposed STGTN can effectively extract spatiotemporal features of rs-fMRI. Furthermore, to solve the sample-limited problem and to improve the anti-noise ability of the proposed model, an adversarial training strategy is adopted for the proposed STGTN to generate adversarial examples (AEs) and augment training samples with AEs. Experimental results indicate that the proposed model achieves the classification accuracy of 92.58%, and 85.27% with the adversarial training strategy for AD vs. normal control (NC), early mild cognitive impairment (eMCI) vs. late mild cognitive impairment (lMCI) respectively, outperforming the state-of-the-art methods. Besides, the spatial attention coefficients reflected from the designed model reveal the importance of brain connections under different classification tasks.

Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy.

Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.