Preclinical Phase Research Articles

The preclinical discovery and development of deucravacitinib for the treatment of psoriasis

ABSTRACT Introduction Psoriasis is a chronic inflammatory skin disease that most commonly presents as plaque psoriasis. The understanding of the pivotal pathogenetic role of the IL-23/IL-17 axis has dramatically changed the therapeutic approach to the disease. The identification of intracellular signaling pathways mediating IL-23 activity provided the rationale for targeting TYK2. Areas covered This review assesses the underlying rationale that led to development of deucravacitinib, a novel oral TYK2 inhibitor, as a therapeutic option for the treatment of moderate-to-severe psoriasis, primarily focusing on pre-clinical and early phase clinical studies. Expert opinion Innovative therapies used in patients with moderate-to-severe psoriasis include biologic agents and small molecules, which are associated with less adverse events than traditional systemic agents. Deucravacitinib, which selectively targets TYK2, has demonstrated to be effective in treating psoriasis, preserving a more favorable safety profile compared to other JAK inhibitors approved for the treatment of other immune diseases that block the ATP-binding site. Because of its oral administration, deucravacitinib represents an intriguing option in the therapeutic armamentarium of psoriasis, though the evaluation of long-term efficacy and safety is necessary to establish its place-in-therapy.

RNA Vaccines: Yeast as a Novel Antigen Vehicle.

In the last decades, technological advances for RNA manipulation enabled and expanded its application in vaccine development. This approach comprises synthetic single-stranded mRNA molecules that direct the translation of the antigen responsible for activating the desired immune response. The success of RNA vaccines depends on the delivery vehicle. Among the systems, yeasts emerge as a new approach, already employed to deliver protein antigens, with efficacy demonstrated through preclinical and clinical trials. β-glucans and mannans in their walls are responsible for the adjuvant property of this system. Yeast β-glucan capsules, microparticles, and nanoparticles can modulate immune responses and have a high capacity to carry nucleic acids, with bioavailability upon oral immunization and targeting to receptors present in antigen-presenting cells (APCs). In addition, yeasts are suitable vehicles for the protection and specific delivery of therapeutic vaccines based on RNAi. Compared to protein antigens, the use of yeast for DNA or RNA vaccine delivery is less established and has fewer studies, most of them in the preclinical phase. Here, we present an overview of the attributes of yeast or its derivatives for the delivery of RNA-based vaccines, discussing the current challenges and prospects of this promising strategy.

TIPS-11 EFFICACY AND SAFETY OF STUPP REGIMEN WITH OR WITHOUT ANLOTINIB FOR NEWLY DIAGNOSED GLIOBLASTOMA: INTERIM RESULTS OF A MULTICENTER, DOUBLEBLIND, RANDOMIZED PHASE II TRIAL

Abstract BACKGROUND Postoperative radiotherapy with concomitant temozolomide (TMZ) followed by ≤ six cycles of adjuvant TMZ chemotherapy (STUPP regimen) is the standard treatment for newly diagnosed glioblastoma (GBM) with limited effectiveness. Anlotinib inhibits both tumor angiogenesis and tumor cell proliferation by targeting multiple kinases, and showing promising results in preclinical GBM models and phase I clinical trials. We designed a phase II trial to verify the efficacy and safety of the STUPP regimen plus anlotinib (NCT 04959500). METHODS This is a multicenter, double-blind, randomized, placebo-controlled trial with an expected 150 patients randomly assigned 1:1 ratio to receive TMZ-based radiochemotherapy with anlotinib or placebo. Major eligibility criteria include histologically confirmed newly diagnosed GBM and an ECOG performance score ≤2. Other criteria for inclusion include age ≥18 years and lack of significant comorbidity. The primary endpoint is the median progression-free survival (PFS). Secondary endpoints include 1-year overall survival rate, PFS at 6 months, overall response rate, duration of response, disease control rate, quality of life, and toxicity. RESULTS From July 2021 to February 8th 2023, 147 patients were enrolled. The results in this abstract were all obtained without exposing the blind state. The median PFS was 9.9 months (95% CI, 9.5-11.9) in the overall patient population, while the predicted mPFS of placebo group was 7 months according to the results of STUPP and AVAGlio trials. Grade 1 (72.82%) and grade 2 (24.27%) adverse events (AEs) were mainly observed, while grade 3 or worse AEs accounted for 2.9% among all AEs. The most frequent TRAEs were lymphocytopenia, decreased platelet count, decreased white blood cell count, decreased neutrophil count and hypertension. Two death cases occurred due to COVID-19 and severe pneumonia. CONCLUSIONS Under the condition of data blinding, these interim results suggest that the STUPP regimen with anlotinib demonstrate potential promising efficacy and a tolerable safety.

The use of radiomics in magnetic resonance imaging for the pre-treatment characterisation of breast cancers: A scoping review.

Radiomics is an emerging field that aims to extract and analyse a comprehensive set of quantitative features from medical images. This scoping review is focused on MRI-based radiomic features for the molecular profiling of breast tumours and the implications of this work for predicting patient outcomes. A thorough systematic literature search and outcome extraction were performed to identify relevant studies published in MEDLINE/PubMed (National Centre for Biotechnology Information), EMBASE and Scopus from 2015 onwards. The following information was retrieved from each article: study purpose, study design, extracted radiomic features, machine learning technique(s), sample size/characteristics, statistical result(s) and implications on patient outcomes. Based on the study purpose, four key themes were identified in the included 63 studies: tumour subtype classification (n = 35), pathologically complete response (pCR) prediction (n = 15), lymph node metastasis (LNM) detection (n = 7) and recurrence rate prediction (n = 6). In all four themes, reported accuracies widely varied among the studies, for example, area under receiver characteristics curve (AUC) for detecting LNM ranged from 0.72 to 0.91 and the AUC for predicting pCR ranged from 0.71 to 0.99. In all four themes, combining radiomic features with clinical data improved the predictive models. Preliminary results of this study showed radiomics potential to characterise the whole tumour heterogeneity, with clear implications for individual-targeted treatment. However, radiomics is still in the pre-clinical phase, currently with an insufficient number of large multicentre studies and those existing studies are often limited by insufficient methodological transparency and standardised workflow. Consequently, the clinical translation of existing studies is currently limited.

Factors That Enhance and Hinder the Retention and Transfer of Online Pre-Clinical Skills Training to Facilitate Blended Learning.

During the SARS-CoV-2 pandemic, various online instructional strategies in clinical skills training were piloted. The sudden transition to the remote platform circumvented the rigorous planning associated with curriculum reform. This study aimed to explore students' and tutors' perceptions of factors that promoted or hindered successful learning transfer and to propose a blended conceptual model to guide affective, cognitive, and psychomotor clinical skills training in the pre-clinical phase of medical education. A mixed-method quasi-experimental study assessed third-year students' transfer of clinical skills and knowledge following online learning in 2021. Students and their tutors completed online surveys that included open and closed-ended questions regarding factors influencing their experience of the adapted teaching methods. Descriptive statistical analysis was used for the quantitative data. Qualitative responses were thematically analyzed. One hundred fourteen students (48%) and seven tutors (100%) responded to the surveys. The questionnaires' internal consistency and construct validity were determined using Cronbach's α-Coefficient. There was an overall positive response (86%) to the acceptability of the online platform in clinical skills training. Using online simulations with targeted onsite practice was reported as effective in clinical skills training. Tutors perceived students as well-prepared for the skills laboratory. Five emergent themes, qualified by a linear model of asynchronous and synchronous online and onsite teaching with the evaluation of the instructional design and institutional support, informed the proposed blended learning guide for clinical skills training in the pre-clinical phase. Blended clinical skills learning that included the flipped classroom concept was well-accepted. Virtual patients proved a convenient cognitive preparation tool for skills training and potentially optimized teaching delivery. The study found that the adapted teaching frameworks incorporating an online clinical skills component into a modified onsite curriculum augmented learners' ability to transfer knowledge to the clinical skills laboratory. An integrated five-step blended model is proposed for future interventions.

Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer.

Immune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, the role of ICI in patients with early-stage, operable CRC remains unclear. The aim of this study was to investigate trials on neoadjuvant ICI in operable CRC. Scoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on neoadjuvant ICI for operable CRC was done up to December 2022. Some 40 trials investigating neoadjuvant ICI for early-stage, operable CRC were identified, including five published trials and three conference abstracts. Preclinical phase I/II trial predominated with only three clinical phase III trials. Few trials investigated neoadjuvant ICI as the only intervention (monotherapy). Trials in rectal cancer were designed for combined ICI with chemo(radio)therapy, only 8 trials stating an MSI/dMMR status for inclusion, one designed for MSS/pMMR only and, the rest agnostic for MMR status. Thirty-eight (95%) trials investigated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PD-1/PD-L1 inhibitors were combined with vascular endothelial growth factor (VEGF) inhibitor or with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, in two trials each, respectively. Pathological complete response as primary outcome after surgery was the most frequently used study endpoint. In rectal cancer, six trials included a "watch and wait" strategy for patients with complete clinical response. No "watch and wait" study design for colon cancer after neoadjuvant ICI were identified. High response rates from neoadjuvant ICI in early-stage colon and rectal cancer are reported in phase I/II studies. Contemporary trial designs are heterogeneous, with few comparable inclusion criteria, use of several drug combinations and durations and, wide variation of endpoints reported. Harmonizing clinical and translational aspects including survival data is needed for improved future trial designs with clinical impact.

Role of Neuropsychological Tests in Early Detection of Alzheimer's Disease

Longitudinal studies using neuropsychological tests have reported that cognitive changes may be observed up to 20 years before diagnosis of dementia. These findings suggest that neuropsychological tests may serve as potential screening tools during the preclinical phase of Alzheimer's disease. However, routine cognitive screening tests show limited sensitivity for prediction of dementia. Therefore, careful selection of appropriate neuropsychological tests is essential for effective screening of dementia during the preclinical stages.

Otoferlin as a multirole Ca2+ signaling protein: from inner ear synapses to cancer pathways.

Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca2+-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca2+-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca2+ signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.

Potential diagnostic value of CSF metabolism-related proteins across the Alzheimer’s disease continuum

BackgroundAlzheimer’s disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aβ42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease.MethodsCSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups.ResultsCSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups.UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers.ConclusionsOur study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD.

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Assessment of Knowledge and Perception Regarding Deep Brain Stimulation Among Medical Students in Saudi Arabia.

Deep brain stimulation (DBS) is a neurosurgical procedure approved for treating psychiatric and movement disorders, including Parkinson's disease (PD), essential tremor, dystonia, and other neurological conditions. The widespread use of DBS may not be reflected in the medical education curricula in Saudi universities, thus jeopardizing future patients' access to it. This study aims to investigate the knowledge and attitudes of medical students toward DBS as a therapeutic option. A descriptive cross-sectional questionnaire-basedstudy was conducted. The survey was distributed on online platforms to acquire responses from different regions of Saudi Arabia. The target population was medical students in the preclinical and clinical phases of medical education from different regions of Saudi Arabia. A total of 1075 medical students from various medical schools in Saudi Arabia were included. More than half of the students aged 21 to 23 (50.1%) were females (63.2%). More than half of the students have correctly recognized DBS as aFood and Drug Administration (FDA)-approved treatment (59.7%). Only 20.1% of the students stated that they received adequate education/training about DBS. About 53.8% of the students had self-rated their knowledge as poor, whereas 20.6% had rated their knowledge as good.A negative bias was more observed among the older students and students with a family history of DBS treatment.Half of the participants (54.1%) indicated that DBS is associated with severe adverse effects. A significant association between the level of knowledge about DBS and the academic level was observed. Almost half of the medical students had poor knowledge and unfavorable attitude towardDBS in Saudi Arabia. The current medical curricula are incommensurable with the clinical implications of DBS, which may deny future patients from such an effective therapeutic option. We recommend incorporating DBS teaching sessions to enhance future physicians' awareness and understanding of the benefits of this intervention.

Combination of Immunotherapy and Radiation Therapy in Gastrointestinal Cancers: An Appraisal of the Current Literature and Ongoing Research.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Measuring anti-islet autoimmunity in mouse and human by profiling peripheral blood antigen-specific CD4 T cells.

The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell-dependent disease. Here, peptide-major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and humans. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish the absence of autoimmunity versus disease progression. Activated anti-insulin CD4 T cell were detected not only at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen-specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the preclinical phase of anti-islet autoimmunity.

Dental materials science curriculum in Malaysia: Time for transformation

Introduction: Dental materials science is one of the core courses for Malaysian undergraduate dental programmes, which has been primarily taught through a series of didactic lectures during the preclinical phase. In accordance with the newly revised national competency statement, Malaysian dental education is moving toward competency-based education, hence a reformation of the dental materials science curriculum is warranted. Methods: Curriculum design including common teaching, learning and assessments methods for the Malaysian dental materials science were described and analysed. The common practices were reviewed and compared with latest national guidelines and literature. Results: There is yet an initiative to establish a national curriculum for dental materials science. The use of traditional teaching strategies for this course also needs to be revamped from a teacher-centred to a student-centred approach. Furthermore, faculty members are facing significant challenges because the revamp requires them to explore cutting-edge pedagogical methods and develop appropriate learning opportunities, environments, resources, and assessments. Several recommendations are proposed, such as mapping the existing dental materials science curriculum to identify gaps, incorporating more hands-on sessions, implementing an integrated curriculum, introducing various formative and summative assessments, as well as recruiting faculty members with different areas of educational expertise. Conclusion: It is hoped that this article offers a clearer pathway for Malaysian dental educators to pioneer new insight and transform the existing dental materials science curriculum.

The Gut Microbiome, a Possible Key to Multidisciplinary Clinical Practice - Literature Review

Abstract Modern medicine tends to evolve towards interdiciplinary collaboration and case management. A strong example in that direction is represented by neurogastroenterology, a field that developed arround the concept of gut-brain axis. Still, research in this field determend the multisystemic role of the gut microbiome, beyond it's regulatory function within the gut-brain axis. The purpose of this review is to focus on the current knowledge in medical literature regarding gut microbiome and its possible invovlvement in medical areas, such as cardiology, rheumatology, pneumology, neurology and psychiatry, bringing these domains closer then ever. We researched Google Scholar, Scopus, PubMed and Wiley Library for articles containing the following key words: “microbiota”, “intestinal bacteria”, “disbiosis”, “probiotics”, “prebiotics”, “rheumatology”, “cardiology”, “diabetes”, “metabolic disease”, “clinical medicine” “cardiology”, “cardiovascular”. Articles were selected by number of acceses, citations, results and by being published between 2015 and 2023. Both animal and clinical studies were considered as well as literature reviews and systematic reviews. Although many studies are still in preclinical phase, and some of them still have uneven results, the road for research has contured theories, especially regarding physiologic and pathophysiologic functions that involve the microbiome and have multisystemic consequences. Conclusions. The gut microbiome may be the key of understanding multi-organic pathophysiologic mechanisms and may have the potential to act as a preventive clinical instrument and raising the effectiveness of therapeutic management in multiple medical fields, not only in gastroenterology and neuropsychiatry.

Defining the presymptomatic phase of frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapies trials are mostly focused on the symptomatic phase, future studies will move earlier in the disease aiming to prevent symptom onset. This review summarizes the recent work to better understand this presymptomatic period. The presymptomatic phase can be split into preclinical and prodromal stages. The onset of the preclinical phase is defined by the first presence of pathological inclusions of tau, TDP-43 or fused in sarcoma in the brain. Definitive biomarkers of these pathologies do not yet exist for FTD. The prodromal phase is defined by the onset of mild symptoms. Recent work has highlighted the wide phenotypic spectrum that occurs, with the concept of mild cognitive ± behavioural ± motor impairment (MCBMI) being put forward, and additions to scales such as the CDR plus NACC FTLD now incorporating neuropsychiatric and motor symptoms. It will be important to better characterize the presymptomatic period moving forward and develop robust biomarkers that can be used both for stratification and outcome measures in prevention trials. The work of the FTD Prevention Initiative aims to facilitate this by bringing together data from natural history studies across the world.

APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice

Vascular factors are known to be early and important players in Alzheimer’s disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

Heparin interferes with the uptake of liposomes in glioma

In glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors influencing cellular uptake of liposomes in glioma cells are poorly understood. Heparin and heparin analogues are commonly used in glioma patients to decrease the risk of thrombo-embolic events. Our results show that heparin inhibits pegylated liposome uptake by U87 glioma and GL261 cells in a dose dependent manner in vitro, and that heparin-mediated inhibition of uptake required presence of fetal bovine serum in the media. In a subcutaneous model of glioma, Cy5.5 labeled liposomes could be detected with in vivo imaging after direct intra-tumoral injection. Ex-vivo analysis with flow cytometry showed a decreased uptake of liposomes into tumor cells in mice treated systemically with heparin compared to those treated with vehicle only.

Developing Vaccines to Improve Preparedness for Filovirus Outbreaks: The Perspective of the USA Biomedical Advanced Research and Development Authority (BARDA).

Outbreaks of viral hemorrhagic fever caused by filoviruses have become more prevalent in recent years, with outbreaks of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV) all occurring in 2022 and 2023. While licensed vaccines are now available for EBOV, vaccine candidates for SUDV and MARV are all in preclinical or early clinical development phases. During the recent outbreak of SUDV virus disease, the Biomedical Advanced Research and Development Authority (BARDA), as part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, implemented key actions with our existing partners to advance preparedness and enable rapid response to the outbreak, while also aligning with global partners involved in the implementation of clinical trials in an outbreak setting. Beyond pre-existing plans prior to the outbreak, BARDA worked with product sponsors to expedite manufacturing of vaccine doses that could be utilized in clinical trials. While the SUDV outbreak has since ended, a new outbreak of MARV disease has emerged. It remains critical that we continue to advance a portfolio of vaccines against SUDV and MARV while also expediting manufacturing activities ahead of, or in parallel if needed, outbreaks.

Application and validation of an algorithmic classification of early impairment in cognitive performance

Objective Due to the long prodromal period for dementia pathology, approaches are needed to detect cases before clinically recognizable symptoms are apparent, by which time it is likely too late to intervene. This study contrasted two theoretically-based algorithms for classifying early cognitive impairment (ECI) in adults aged ≥50 enrolled in the Baltimore Longitudinal Study of Aging. Method Two ECI algorithms were defined as poor performance (1 standard deviation [SD] below age-, sex-, race-, and education-specific means) in: (1) Card Rotations or California Verbal Learning Test (CVLT) immediate recall and (2) ≥1 (out of 2) memory or ≥3 (out of 6) non-memory tests. We evaluated concurrent criterion validity against consensus diagnoses of mild cognitive impairment (MCI) or dementia and global cognitive scores using receiver operating characteristic (ROC) curve analysis. Predictive criterion validity was evaluated using Cox proportional hazards models to examine the associations between algorithmic status and future adjudicated MCI/dementia. Results Among 1,851 participants (mean age = 65.2 ± 11.8 years, 50% women, 74% white), the two ECI algorithms yielded comparably moderate concurrent criterion validity with adjudicated MCI/dementia. For predictive criterion validity, the algorithm based on impairment in Card Rotations or CVLT immediate recall was the better predictor of MCI/dementia (HR = 3.53, 95%CI: 1.59–7.84) over 12.3 follow-up years. Conclusions Impairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.