Evaluation Of Treatment Efficacy Research Articles

Clinical characteristics and survival of patients with de novo metastatic prostate cancer treated with androgen deprivation therapy and taxane-based chemotherapy in Uganda: a retrospective study.

Prostate cancer is the second most common cancer among men worldwide. Mortality is highest among patients in resource-limited settings (RLS), in part due to late-stage disease. Among patients with metastatic prostate cancer (mPCa), studies have shown significant improvement in overall survival with the use of androgen deprivation therapy (ADT) and taxane-based chemotherapy. However, outcome data among patients treated with chemo-endocrine therapy are scarce in many resource-limited settings. The aim of this study was to determine the clinical characteristics and 5-year overall survival (OS) of patients with de novo mPCa treated at the Uganda Cancer Institute (UCI). A retrospective chart review study was conducted between 2015 and 2019, and the data of patients with histologically confirmed prostate cancer and radiological evidence of metastasis were reviewed. Sample size was estimated for Cox Proportion Hazard regression. Data on clinical and laboratory characteristics, overall survival, and predictors of survival were extracted. P < 0.05 was considered to indicate statistical significance. A total of 300 patients were enrolled over the 5-year study period. The median age was 68 (IQR 61.5-74) years. At presentation, lower urinary tract symptoms were reported in nearly all patients (96.7%, n = 290), median total prostate specific antigen (PSA) was 414.75 ng/ml and 40% (n = 120) of patients had grade 5 histological scores. In addition to receiving ADT, majority of patients (70.3%, n = 211) received at least 6 cycles of chemotherapy. Overall survival at one year was 92.4% (95% CI: 88.6-94.9%), but it declined to 45.2% (95% CI: 36.8-53.2%) at 5 years. A high Gleason score, the presence of visceral metastasis and receiving less than 6 cycles of chemotherapy were predictors of poor outcomes. Patients with de novo mPCa in Uganda present with high histologic grades and high baseline Prostate Specific Antigen (PSA) levels but have improved 5-year overall survival with a combination of chemotherapy and ADT as a first-line treatment. We recommend interventions to reduce late presentation and prospective studies to evaluate treatment efficacy in this population.

Abstract B032: Genome-wide 5-hydroxymethylation mapping in cell-free DNA to characterize the epigenetic differences in minimal residual disease of multiple myeloma

Abstract Background: Multiple myeloma (MM), a B-cell neoplasm characterized by the infiltration of malignant plasma cells into the bone marrow, is the second most common blood malignancy in the United States. The molecular pathogenesis of MM involves both genetic and epigenetic alterations. While 60-75% of newly diagnosed patients achieve a complete response or better with current modern combination therapies, almost all patients eventually progress largely due to the persistence or re-emergence of minimal residual disease (MRD). Monitoring for MRD has become essential for evaluating treatment efficacy and predicting long-term outcomes in MM patients. We aimed to investigate whether epigenetic changes, particularly 5- hydroxymethylcytosines (5hmC), at diagnosis are associated with MRD status following treatment. Methods: Utilizing 5hmC-Seal, a highly sensitive chemical labeling technique, we profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) and bone marrow genomic DNA (gDNA) at baseline and after 8 cycles of treatment (C8) from newly diagnosed MM patients (n=25) enrolled in a clinical trial (NCT01816971). MRD testing was performed on bone marrow samples using the clonoSEQ next generation sequencing assay (limit of detection 10-6). Results: The 5hmC modification levels were summarized across various genomic features, revealing enrichment in gene bodies and enhancer regions, consistent with the known regulatory role of 5hmC. We ranked 5hmC-modified genes at baseline by their variability, and found that the number of overlapping genes between cfDNA and gDNA was significantly higher than expected by permutation analysis. Subsequently, we identified the top 100 most variable 5hmC- modified genes in gDNA, which exhibited a higher Pearson correlation with cfDNA within individuals (mean r=0.90) compared to between individuals (mean r=0.82; p&amp;lt;0.05), suggesting that cfDNA has the potential to reflect gDNA in capturing some MM-related variations. Among the 11 patients with MRD+ at C8, a genome-wide scan of 5hmC in cfDNA comparing baseline and C8 identified 1,614 differentially modified genes (p&amp;lt;0.05) after adjusting for age and sex. [BC1] Furthermore, we identified 459 differentially modified genes comparing baseline 5hmC levels between patients who were MRD+ (n=11) and MRD- (n= 14) at C8 (p&amp;lt;0.05), after adjusting for age and sex. These results highlight the differential epigenetic landscape associated with MRD status. Conclusions: Genome-wide 5hmC profiling of cfDNA from blood revealed a similar epigenetic landscape to gDNA from bone marrow in patients with MM, suggesting that cfDNA may offer a less invasive alternative for assessing epigenetic modifications. Moreover, this profiling identified distinct epigenetic changes associated with the achievement of MRD- negativity. These findings provide a foundation for further investigation into the molecular alterations linked to MM disease biology that could potentially lead to MRD negativity. Future directions will focus on identifying biomarkers that could inform personalized treatment strategies. Citation Format: Zhou Zhang, Bei Wang, Krissana Kowitwanich, John Cursio, Daniel Appelbaum, Chuan He, Wei Zhang, Benjamin Derman, Brian Chiu, Andrzej Jakubowiak. Genome-wide 5-hydroxymethylation mapping in cell-free DNA to characterize the epigenetic differences in minimal residual disease of multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B032.

Changes in skin barrier integrity by electrical impedance spectroscopy during dupilumab treatment on a child with severe atopic dermatitis

Background. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal skin barrier dysfunction and altered immune response. Electrical impedance spectroscopy (EIS) has been used as a novel tool to detect skin barrier changes in AD. EIS is a non-invasive measure of the electrical impedance of tissue and is sensitive to cellular structure and extracellular environment. Case Presentation. An 8-year-old girl presented with severe AD, starting at 3 years of age. She also had allergic rhinitis, food allergies, and sensitization to mites, eggs, and nuts. Unresponsive to other treatments, she was administered 300 mg of dupilumab, a monoclonal antibody inhibiting IL-4 and IL-13 activity. Patient’s response to the treatment and skin barrier integrity was followed for 6 months: First at the baseline (before dupilumab) and then again at the 1st, 2nd, 3rd, and 5.5th month after dupilumab with SCORing Atopic Dermatitis (SCORAD), as well as measurements of moisture by MoistureMeterSC (Delfin®) and EIS by Nevisense® (SciBase) on the forearm and antecubital fossa of the same arm. At the end of 6 months, her SCORAD improved from 96 to 37. The moisture measurements were variable. The EIS by Z1 score in the forearm increased from 72 to 141 and EIS by MIX scores increased from 2.7 to 6.2. The correlation between SCORAD and forearm EIS by Z1 and MIX scores were significant: r=-0.913, (p=0.03) and r=-0.881, (p=0.049). The correlation between forearm MIX scores with sleeplessness and itching was significant: r=-0.956, (p=0.011), r=-0.942, (p=0.017). Conclusion. As higher EIS scores reflect stronger barrier integrity, the increase in Z1 and MIX obtained from Nevisense® implies an improvement in the skin barrier integrity during dupilumab treatment. This report highlights the potential use of EIS in atopic dermatitis patients to evaluate treatment efficacy. We urge rapid and non-invasive use of EIS in pediatrics to be further investigated in clinical settings.

Changes in lipid abundance are associated with disease progression and treatment response in chronic Trypanosoma cruzi infection

BackgroundChagas disease, caused by the parasite Trypanosoma cruzi, is a zoonosis that affects more than seven million people. Current limitations on the diagnosis of the disease hinder the prognosis of patients and the evaluation of treatment efficacy, slowing the development of new therapeutic options. The infection is known to disrupt several host metabolic pathways, providing an opportunity for the identification of biomarkers.MethodsThe metabolomic and lipidomic profiles of a cohort of symptomatic and asymptomatic patients with T. cruzi infection and a group of uninfected controls were analysed using liquid chromatography/mass spectrometry. Differences among all groups and changes before and after receiving anti-parasitic treatment across those with T. cruzi infection were explored.ResultsThree lipids were found to differentiate between symptomatic and asymptomatic participants: 10-hydroxydecanoic acid and phosphatidylethanolamines PE(18:0/20:4) and PE(18:1/20:4). Additionally, sphinganine, 4-hydroxysphinganine, hexadecasphinganine, and other sphingolipids showed post-treatment abundance similar to that in non-infected controls.ConclusionsThese molecules hold promise as potentially useful biomarkers for monitoring disease progression and treatment response in patients with chronic T. cruzi infection.Graphical

Potential Disease-Modifying Effects of Ganglioside GM1 Pulse Treatment on Spinocerebellar Ataxia Type 3, a Parallel-Group, Double-Blind, Randomized, Controlled Trial.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy. Our aim was to investigate the safety and efficacy of high-dose ganglioside GM1 (ganglioside-monosialic acid) pulse treatment in patients with SCA3. Patients were randomly allocated to receive either high-dose GM1 (400 mg on the first day followed by 200 mg/day), low-dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post-treatment, is central to evaluating treatment efficacy. Secondary outcomesincluded changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients. A total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention-to-treat analysis). The least-squares mean change in the SARA score from baseline to 12 weeks post-treatment was -3.80 (standard error [SE], 0.39; 95% confidence interval [CI], -4.58 to -3.02) in the high-dose GM1 group, 0.34 (SE, 0.40; 95% CI, -0.46 to 1.13) in the low-dose GM1 group, and 0.73 (SE, 0.40; 95% CI, -0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high-dose GM1 group compared to the low-dose GM1 and placebo groups. All treatments were well-tolerated and safe. High-dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. © 2024 International Parkinson and Movement Disorder Society.

First-in-Human Abdominal Aortic Aneurysms Trial with Tricaprin (F-HAAAT): Study Design and Protocol

Approximately 2–12% of individuals aged > 65 years worldwide are estimated to have an abdominal aortic aneurysm (AAA), with a mortality rate exceeding 60% in rupture cases. The sole preventive intervention against rupture is timely surgery, which requires substantial medical resources, including postoperative complication management. Although numerous randomized clinical trials have been performed, no oral medication effectively treats AAA. Tricaprin, a medium-chain triglyceride (MCT) with three capric acids, is used in dietary therapy for metabolic and neurological disorders. Our group recently reported that tricaprin, unlike other MCTs, showed reverse remodeling of AAA in a rat model. Determining whether this basic finding could be translated to clinical practice is important. The First-in-Human Abdominal Aortic Aneurysms trial with Tricaprin (F-HAAAT) proposes the first-in-human AAA trial to confirm the safety of tricaprin in patients with small AAA, exploring novel assessment methods to evaluate treatment efficacy. This single-center, open-label, single-arm study will include ten patients (aged 50–85 years) with small AAA (30–45 mm in diameter) receiving daily oral tricaprin (1.5–3.0 g/day) for 52 weeks. Primary endpoints include safety evaluation of tricaprin determined by monitoring all adverse events, particularly major adverse cardiovascular events, AAA-related adverse events, and other unpredictable events. Secondary endpoints include parameters to validate tricaprin efficacy by measuring AAA diameter, volume, and Agatston score, and analyzing computed tomography values of the aortic aneurysmal wall. F-HAAAT outcomes may provide insights into noninvasive methods for indirectly analyzing AAA pathological characteristics and revealing aneurysmal reverse remodeling. (jRCTs051240036, Japan Registry of Clinical Trials)

Research on the prognosis and efficacy criteria of sudden sensorineural hearing loss

Sudden sensorineural hearing loss is a common and frequently-occurring disease. Looking at the efficacy evaluation of the diagnosis and treatment of sudden sensorineural hearing loss at home and abroad, each country has its own characteristics in the indicators and criteria of the treatment efficacy evaluation, and the common indicators of efficacy evaluation include: average pure-tone hearing threshold, the absolute value of hearing improvement of impaired frequency, the percentage of average pure-tone hearing threshold increase, speech discrimination score, speech recognition threshold, etc. The evaluation criteria mostly take the efficacy grade or the improvement level of average hearing threshold as the criterion of effective treatment, and the lack of unified standards is not conducive to the homogenization of global research related to sudden sensorineural hearing loss. In order to provide reference for the clinical evaluation of sudden sensorineural hearing loss in China, this study systematically reviewed the clinical practice guidelines and the evaluation indexes and criteria of clinical efficacy in high quality clinical multicenter studies of the disease in many countries.

Somatic mutational landscape reveals mutational signatures and significantly mutated genes of cancer immunotherapeutic outcome and sex disparities

BackgroundCurrently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators.MethodsWe integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments.ResultsWe found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences.ConclusionThis study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.

Application of artificial intelligence to study the causality in public health: a systematic review

Abstract Introduction In epidemiology, establishing causation requires meeting rigorous criteria beyond mere association. Traditional methodologies often struggle to provide definitive causal conclusions due to confounding variables. However, leveraging artificial Intelligence (AI) and machine Learning (ML) offers a promising solution by modeling complex interactions among relevant factors. This systematic review explores the AI techniques utilized to uncover causal relationships in public health applications. Methods A literature search was conducted in Pubmed, Web of Science, and Scopus, employing the following search strategy: (Causalit*[Title/abstract] OR Causation*[Title/abstract] OR Causal[Title/abstract]) AND (‘Machine Learning’[Title/abstract] OR “Deep Learning” [Title/abstract] OR ‘Artificial Intelligence’ [Title/abstract] OR Algorithm* [Title/abstract]). The search aimed to identify studies encompassing causal inference techniques utilizing ML and AI methodologies in public health. Results From a total of 28,230 articles published up to August 2023, after removing duplicates (11,158) and articles that did not meet the inclusion criteria (16,168 post title/abstract screening, and 856 post full-text screening), the systematic review included 48 articles. Bayesian additive regression trees, Bayesian network models, causal forests analysis, and graphical causal models emerged as the prevailing causal methodologies. AI-driven causal methodologies have been investigated across various domains within public health, encompassing disease prediction, evaluation of treatment efficacy, identification of risk factors, analysis of health behaviors, precision Public Health initiatives, and environmental health assessment. Discussion While our systematic review affirms the potential of AI-driven causal approaches across several public health domains, further research is warranted before these emerging techniques can be effectively integrated into real settings. Key messages • In epidemiology, establishing causation requires meeting rigorous criteria beyond mere association and traditional methodologies often struggle to provide definitive causal conclusions. • This systematic review explores the AI techniques utilized to uncover causal relationships in public health applications.

Tumor therapeutics in the era of "RECIST": past, current insights, and future prospects.

In recent years, advancements in medical treatment and imaging technologies have revolutionized the assessment of tumor response. However, the Response Evaluation Criteria in Solid Tumors (RECIST) has long been established as the gold standard for evaluating tumor treatment. As treatment modalities evolve, the need for continuous refinement and adaptation of RECIST becomes increasingly apparent. This review explores the historical evolution, current applications, limitations, and future directions of RECIST. It discusses the challenges of distinguishing true progression from pseudo-progression in ICIs (immune checkpoint inhibitors), the integration of advanced imaging tools, and the necessity for RECIST criteria tailored to specific therapies like neoadjuvant treatments. The review highlights the ongoing efforts to enhance RECIST's accuracy and reliability in clinical decision-making and the potential for developing new standards to better evaluate treatment efficacy in the rapidly evolving landscape of oncology.

Development of bioluminescent Group B streptococcal strains for longitudinal infection studies.

Group B Streptococcus (GBS) remains the leading bacterial cause of invasive neonatal disease, resulting in substantial morbidity and mortality. New therapeutic approaches beyond antibacterial treatment to prevent neonatal disease outcomes are urgent. One significant limitation in studying GBS disease and progression is the lack of non-invasive technologies for longitudinal studies. Here, we develop and compare three bioluminescent GBS strains for in vivo pathogenic analysis. Bioluminescence is based on the luxABCDE operon on a replicative vector (luxGBS-CC17), and the red-shifted firefly luciferase on a replicative vector (fflucGBS-CC17) or integrated in the genome (glucGBS-CC17). We show that luxGBS-CC17 is suitable for in vitro analysis but does not produce a significant bioluminescent signal in infected pups. In contrast, the fflucGBS-CC17 results in a strong bioluminescent signal proportional to the organ colonisation level. However, the stability of the replicative vector depends on the route of infection, especially when pups acquire the bacteria from infected vaginal mucosa. Stable chromosomal integration of luciferase in glucGBS-CC17 leads to significant bioluminescence in both haematological and vertical infection models associated with high systemic colonisation. These strains will allow the preclinical evaluation of treatment efficacy against GBS invasive disease using whole-mouse bioluminescence imaging.

Strategic Integration: A Cross-Disciplinary Review of the fNIRS-EEG Dual-Modality Imaging System for Delivering Multimodal Neuroimaging to Applications.

Background: Recent years have seen a surge of interest in dual-modality imaging systems that integrate functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) to probe brain function. This review aims to explore the advancements and clinical applications of this technology, emphasizing the synergistic integration of fNIRS and EEG. Methods: The review begins with a detailed examination of the fundamental principles and distinctive features of fNIRS and EEG techniques. It includes critical technical specifications, data-processing methodologies, and analysis techniques, alongside an exhaustive evaluation of 30 seminal studies that highlight the strengths and weaknesses of the fNIRS-EEG bimodal system. Results: The paper presents multiple case studies across various clinical domains-such as attention-deficit hyperactivity disorder, infantile spasms, depth of anesthesia, intelligence quotient estimation, and epilepsy-demonstrating the fNIRS-EEG system's potential in uncovering disease mechanisms, evaluating treatment efficacy, and providing precise diagnostic options. Noteworthy research findings and pivotal breakthroughs further reinforce the developmental trajectory of this interdisciplinary field. Conclusions: The review addresses challenges and anticipates future directions for the fNIRS-EEG dual-modal imaging system, including improvements in hardware and software, enhanced system performance, cost reduction, real-time monitoring capabilities, and broader clinical applications. It offers researchers a comprehensive understanding of the field, highlighting the potential applications of fNIRS-EEG systems in neuroscience and clinical medicine.

Seeding Aggregation Assays in Lewy Bodies Disorders: A Narrative State-of-the-Art Review

Multiple system atrophy and Lewy body diseases (LBDs) such as Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with dementia, known as synucleinopathies, are defined neuropathologically by the accumulation and deposition of aberrant protein aggregates, primarily in neuronal cells. Seeding aggregation assays (SAA) have significant potential as biomarkers for early diagnosis, monitoring disease progression, and evaluating treatment efficacy for these diseases. Real-time quaking-induced conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) assays represent two ultrasensitive protein amplification techniques that were initially tested for the field of prion disorders. Although the fundamental idea behind the creation of these two methods is very similar, their technical differences resulted in different levels of diagnostic accuracy for the identification of prion proteins, making the RT-QuIC assay the most trustworthy and effective instrument for the detection of suspected cases of LBDs and prion-like diseases.

Exploring causal association between functional/structural connectivity and major depression disorder: A bidirectional Mendelian randomization study

ObjectivesPrior observational studies have suggested a correlation between major depressive disorder (MDD) and communication imbalances within the resting-state brain network (RSN), but the causal relationship remains unclear. This research uses Mendelian randomization (MR) analysis to explore the potential causal effects between functional connectivity (FC), structural connectivity (SC) and MDD. MethodsTwo-sample bidirectional MR analysis was employed in this study. Inverse variance weighted (IVW) was used to explore the causal relationship between the FC/SC and MDD, with various methods such as MR-Egger to conduct sensitivity analyses. ResultsThe IVW analysis results showed that higher genetic predicted dorsal attention network FC, limbic network SC, and dorsal attention network SC were associated with an increased risk of MDD (β: 15.08, 95%CI: 5.89–24.27, p = 0.001; β: 3.79, 95%CI: −0.22-7.8, p = 0.034; β: 9.89, 95%CI: 0.88–18.90, p = 0.031). Reverse MR analysis demonstrated that a genetically predicted elevated risk of MDD was associated with reduced frontal parietal network FC (β: −0.00046, p = 0.041). ConclusionsThe study suggests a causal relationship between the FC and SC within specific RSNs and the risk of MDD. Abnormalities in the dorsal attention network FC/SC and the limbic network SC were risk factors for MDD. The FC abnormality of the frontal parietal network may be the downstream influence following the MDD onset. Further investigation is needed to determine the potential utility of these neuroimaging markers in the prevention of MDD or the evaluation of treatment efficacy.

Molecular characterization and biomarker identification in paediatric B-cell acute lymphoblastic leukaemia.

B-cell acute lymphoblastic leukaemia (B-ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Managing B-ALL remains challenging due to its heterogeneity and relapse risk. This study aimed to delineate the molecular features of paediatric B-ALL and explore the clinical utility of circulating tumour DNA (ctDNA). We analysed 146 patients with paediatric B-ALL who received systemic chemotherapy. The mutational landscape was profiled in bone marrow (BM) and plasma samples using next-generation sequencing. Minimal residual disease (MRD) testing on day 19 of induction therapy evaluated treatment efficacy. RNA sequencing identified gene fusions in 61% of patients, including 37 novel fusions. Specifically, the KMT2A-TRIM29 novel fusion was validated in a boy who responded well to initial therapy but relapsed after 1 year. Elevated mutation counts and maximum variant allele frequency in baseline BM were associated with significantly poorer chemotherapy response (p = 0.0012 and 0.028, respectively). MRD-negative patients exhibited upregulation of immune-related pathways (p < 0.01) and increased CD8+ T cell infiltration (p = 0.047). Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B-ALL management.

Clinical Study on Mesenchymal Stem Cell Factors Therapy for Alzheimer’s Disease

Background: Alzheimer’s disease (AD), characterized by cognitive decline, lacked effective cures. Mesenchymal stem cell (MSC) factors (MSCFs) offered a new approach by promoting brain tissue repair and modulating immune responses, presenting a promising alternative to AD treatment with minimal risks. Aim: This study aimed to investigate the effects of MSCF on AD and to compare the effects with traditional MSC treatments. Methods: Sixty patients were divided into control and observation groups, with 30 cases in each group. The control group were injected intravenously with 10 mL of MSCs (5.0 × 109 L-1) plus 100 mL normal saline (once every 5 days for six consecutive treatments). The observation group received intramuscular injections of 0.5 mL (1 mL for the first dose) of MSCF (every other day for 15 consecutive treatments). Amyloid-β 42 (Aβ42) and Tau protein concentrations in cerebrospinal fluid were determined by ELISA pretreatment and at 1, 3, and 6 months’ post-treatment. The Clinical Dementia Rating of AD patients was recorded at these intervals to evaluate treatment efficacy. Results: Aβ42 levels increased, and Tau protein levels decreased in both groups. The CDR score dropped post treatment. The total effective rate and clinical cure rate were 86.67% and 6.70% in the control group and 100% and 40% in the observation group, respectively. MSCF and MSCs uniquely impact AD. Conclusion: MSCs contributed to damaged nerve cell repair, new nerve cell differentiation, and the participation of some dormant nerve cells in physiological activity. MSCF offered a small-dose, rapid, and safe treatment with simple operation.

Investigating the Interplay between Cardiovascular and Neurodegenerative Disease.

Neurological diseases, including neurodegenerative diseases (NDDs), are the primary cause of disability worldwide and the second leading cause of death. The chronic nature of these conditions and the lack of disease-modifying therapies highlight the urgent need for developing effective therapies. To accomplish this, effective models of NDDs are required to increase our understanding of underlying pathophysiology and for evaluating treatment efficacy. Traditionally, models of NDDs have focused on the central nervous system (CNS). However, evidence points to a relationship between systemic factors and the development of NDDs. Cardiovascular disease and related risk factors have been shown to modify the cerebral vasculature and the risk of developing Alzheimer's disease. These findings, combined with reports of changes to vascular density and blood-brain barrier integrity in other NDDs, such as Huntington's disease and Parkinson's disease, suggest that cardiovascular health may be predictive of brain function. To evaluate this, we explore evidence for disruptions to the circulatory system in murine models of NDDs, evidence of disruptions to the CNS in cardiovascular disease models and summarize models combining cardiovascular disruption with models of NDDs. In this study, we aim to increase our understanding of cardiovascular disease and neurodegeneration interactions across multiple disease states and evaluate the utility of combining model systems.

Development of a Specifically Labeled 89Zr Antibody for the Noninvasive Imaging of Tumors Overexpressing B7-H3.

B7-H3 has emerged as a promising target and potential biomarker for diagnosing tumors, evaluating treatment efficacy, and determining patient prognosis. Hu4G4 is a recombinant humanized antibody that selectively targets the extracellular domain of human B7-H3. In this study, we describe the radiolabeling of hu4G4 with the positron emission tomography (PET) emitter radionuclide zirconium 89 (89Zr) and evaluate its potency as an immuno-PET tracer for B7-H3-targeted imaging by comparing it in vitro and in vivo to [89Zr]Zr-DFO-DS-5573a using various models. The radiolabeled compound, [89Zr]Zr-desferrioxamine-hu4G4 ([89Zr]Zr-DFO-hu4G4), demonstrated a high radiochemical purity (RCP) of greater than 99% and a specific activity of 74 MBq/mg following purification. Additionally, it maintained stability in human serum albumin (HSA) and acetate buffer, preserving over 90% of its RCP after 7 days. Three cell lines targeting human B7-H3(U87/CT26-CD276/GL261-CD276) were used. Flow cytometry analysis indicated that the B7-H3-positive cells (U87/CT26-CD276/GL261-CD276) had a higher B7-H3 protein level with no expression in the B7-H3-negative cells (CT26-wt/GL261-wt) (P < 0.001). Moreover, the cellular uptake was 45.71 ± 3.78% for [89Zr]Zr-DFO-hu4G4 in CT26-CD276 cells versus only 0.93 ± 0.47% in CT26-wt cells and 30.26 ± 0.70% when [89Zr]Zr-DFO-hu4G4 in CT26-CD276 cells were blocked with 100× 8H9. The cellular uptake of [89Zr]Zr-DFO-hu4G4 was akin to that observed with [89Zr]Zr-DFO-DS-5573a with no significant differences (45.71 ± 3.78 % vs 47.07 ± 0.86 %) in CT26-CD276 cells. Similarly, the CT26-CD276 mouse model demonstrated markedly low organ uptake and elevated tumor uptake 48 h after [89Zr]Zr-DFO-hu4G4 injection. PET/CT analysis showed that the tumor-to-muscle (T/M) ratios were substantially higher compared to other imaging groups: 27.65 ± 3.17 in CT26-CD276 mice versus 11.68 ± 4.19 in CT26-wt mice (P < 0.001) and 16.40 ± 0.78 when 100× 8H9 was used to block [89Zr]Zr-DFO-hu4G4 in CT26-CD276 mice (P < 0.01) at 48 h post-injection. Additionally, the tracer showed markedly high accumulation in the tumor region (22.57 ± 3.03% ID/g), comparable to the uptake of [89Zr]Zr-DFO-DS-5573a (24.76 ± 5.36% ID/g). A dosimetry estimation study revealed that the effective dose for [89Zr]Zr-DFO-hu4G4 was 2.96 × 10-01 mSv/MBq, which falls within the acceptable range for further research in nuclear medicine. Collectively, these results indicated that [89Zr]Zr-DFO-hu4G4 was successfully fabricated and applied in B7-H3-targeted tumor PET/CT imaging, which showed excellent imaging quality and tumor detection efficacy in tumor-bearing mice. It is a promising imaging agent for identifying tumors that overexpress B7-H3 for future clinical applications.

Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool.

CAR T cell therapy has revolutionized the treatment of a spectrum of blood-related malignancies. However, treatment responses vary among cancer types and patients. Accurate monitoring of CAR T cell dynamics is crucial for understanding and evaluating treatment efficacy. Positron emission tomography (PET) offers a comprehensive view of CAR T cell homing, especially in critical organs such as lymphoid structures and bone marrow. This information will help assess treatment response and predict relapse risk. Current PET imaging methods for CAR T require genetic modifications, limiting clinical use. To overcome this, we developed an antigen-based imaging approach enabling whole-body CAR T cell imaging. The probe detects CAR T cells in vivo without affecting their function. In an immunocompetent B cell leukemia model, CAR-PET signal in the spleen predicted early mortality risk. The antigen-based CAR-PET approach allows assessment of CAR T therapy responses without altering established clinical protocols. It seamlessly integrates with FDA-approved and future CAR T cell generations, facilitating broader clinical application.

Measuring clinically relevant change in apathy symptoms in ADMET and ADMET 2.

Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales. Retrospective anchor- and distribution-based analyses of change in apathy symptom scores. Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively. Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease. The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory - Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics. Among the MCID was a decrease of four points (95% CI: -4.0 to -4.8) on the NPI-A, 0.56 points (95% CI: -0.47 to -0.65) on the DAIR, and three points on the AES-I (95% CI: -0.9 to -5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID. MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales.