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Neuroscience May 2024Despite recent advances in acute stroke management, most patients experiencing a stroke will suffer from residual brain damage and functional impairment. Addressing... (Review)
Review
Despite recent advances in acute stroke management, most patients experiencing a stroke will suffer from residual brain damage and functional impairment. Addressing those residual deficits would require neurorestoration, i.e., rebuilding brain tissue to repair the structural brain damage caused by stroke. However, there are major pathobiological, anatomical and technological hurdles making neurorestorative approaches remarkably challenging, and true neurorestoration after larger ischemic lesions could not yet be achieved. On the other hand, there has been steady advancement in our understanding of the limits of tissue regeneration in the adult mammalian brain as well as of the fundamental organization of brain tissue growth during embryo- and ontogenesis. This has been paralleled by the development of novel animal models to study stroke, advancement of biomaterials that can be used to support neurorestoration, and in stem cell technologies. This review gives a detailed explanation of the major hurdles so far preventing the achievement of neurorestoration after stroke. It will also describe novel concepts and advancements in biomaterial science, brain organoid culturing, and animal modeling that may enable the investigation of post-stroke neurorestorative approaches in translationally relevant setups. Finally, there will be a review of recent achievements in experimental studies that have the potential to be the starting point of research and development activities that may eventually bring post-stroke neurorestoration within reach.
PubMed: 38763225
DOI: 10.1016/j.neuroscience.2024.05.009 -
Journal of Translational Medicine May 2024Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for...
BACKGROUND
Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies.
METHOD
The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells.
RESULT
Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway.
CONCLUSION
The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.
Topics: Metaplasia; Humans; Air; Models, Biological; Gastric Mucosa; Stomach; Organoids; Stomach Neoplasms; Gene Expression Regulation, Neoplastic; Transcriptome; Intestines
PubMed: 38760813
DOI: 10.1186/s12967-024-05276-7 -
Cancers Apr 2024Malignant spinal lesions (MSLs) are frequently the first manifestation of malignant disease. Spinal care, diagnostic evaluation, and the initiation of systemic therapy...
A Combined Cyto- and Histopathological Diagnostic Approach Reduces Time to Diagnosis and Time to Therapy in First Manifestation of Metastatic Spinal Disease: A Cohort Study.
Malignant spinal lesions (MSLs) are frequently the first manifestation of malignant disease. Spinal care, diagnostic evaluation, and the initiation of systemic therapy are crucial for outcomes in patients (pts) with advanced cancer. However, histopathology (HP) may be time consuming. The additional evaluation of spinal lesions using cytopathology (CP) has the potential to reduce the time to diagnosis (TTD) and time to therapy (TTT). CP and HP specimens from spinal lesions were evaluated in parallel in 61 pts (CP/HP group). Furthermore, 139 pts in whom only HP was performed were analyzed (HP group). We analyzed the TTD of CP and HP within the CP/HP group. Furthermore, we compared the TTD and TTT between the groups. The mean TTD in CP was 1.7 ± 1.7 days (d) and 8.4 ± 3.6 d in HP ( < 0.001). In 13 pts in the CP/HP group (24.1%), specific therapy was initiated based on the CP findings in combination with imaging and biomarker results before completion of HP. The mean TTT in the CP/HP group was 21.0 ± 15.8 d and was significantly shorter compared to the HP group (28.6 ± 23.3 d) ( = 0.034). Concurrent CP for MSLs significantly reduces the TTD and TTT. As a result, incorporating concurrent CP for analyzing spinal lesions suspected of malignancy might have the potential to enhance pts' quality of life and prognosis in advanced cancer. Therefore, we recommend implementing CP as a standard procedure for the evaluation of MSLs.
PubMed: 38730611
DOI: 10.3390/cancers16091659 -
Chemical Science May 2024Prostate-specific membrane antigen (PSMA) is a tumor-associated protein that has been successfully targeted with small organic ligands and monoclonal antibodies....
Prostate-specific membrane antigen (PSMA) is a tumor-associated protein that has been successfully targeted with small organic ligands and monoclonal antibodies. Pluvicto™ is a PSMA-targeted radioligand therapeutic (RLT) recently approved by the FDA for the treatment of metastatic castration-resistant prostate cancer (2022 FDA marketing authorization). Although a large Phase III clinical trial (VISION trial) demonstrated clinical benefits in patients treated with Pluvicto™, the therapeutic window of the drug is narrowed by its undesired accumulation in healthy organs. Glutamate carboxypeptidase III (GCPIII), an enzyme sharing 70% identity with PSMA, may be responsible for the off-target accumulation of PSMA-RLTs in salivary glands and kidneys. In this work, we designed and synthesized affinity and selectivity maturation DNA-encoded chemical libraries (ASM-DELs) comprising 18'284'658 compounds that were screened in parallel against PSMA and GCPIII with the aim to identify potent and selective PSMA ligands for tumor-targeting applications. Compound A70-B104 was isolated as the most potent and selective ligand ( of 900 pM for PSMA, of 40 nM for GCPIII). Lu-A70-B104-DOTA, a radiolabeled derivative of compound A70-B104, presented selective accumulation in PSMA-positive cancer lesions (, 7.4% ID g, 2 hour time point) after systemic administration in tumor-bearing mice. The results of autoradiography experiments showed that Lu-A70-B104-DOTA selectively binds to PSMA-positive cancer tissues, while negligible binding on human salivary glands was observed.
PubMed: 38725500
DOI: 10.1039/d3sc06668a -
JAMA Ophthalmology Jun 2024Despite widespread availability and consensus on its advantages for detailed imaging of geographic atrophy (GA), spectral-domain optical coherence tomography (SD-OCT)... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Despite widespread availability and consensus on its advantages for detailed imaging of geographic atrophy (GA), spectral-domain optical coherence tomography (SD-OCT) might benefit from automated quantitative OCT analyses in GA diagnosis, monitoring, and reporting of its landmark clinical trials.
OBJECTIVE
To analyze the association between pegcetacoplan and consensus GA SD-OCT end points.
DESIGN, SETTING, AND PARTICIPANTS
This was a post hoc analysis of 11 614 SD-OCT volumes from 936 of the 1258 participants in 2 parallel phase 3 studies, the Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (OAKS) and Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (DERBY). OAKS and DERBY were 24-month, multicenter, randomized, double-masked, sham-controlled studies conducted from August 2018 to July 2020 among adults with GA with total area 2.5 to 17.5 mm2 on fundus autofluorescence imaging (if multifocal, at least 1 lesion ≥1.25 mm2). This analysis was conducted from September to December 2023.
INTERVENTIONS
Study participants received pegcetacoplan, 15 mg per 0.1-mL intravitreal injection, monthly or every other month, or sham injection monthly or every other month.
MAIN OUTCOMES AND MEASURES
The primary end point was the least squares mean change from baseline in area of retinal pigment epithelium and outer retinal atrophy in each of the 3 treatment arms (pegcetacoplan monthly, pegcetacoplan every other month, and pooled sham [sham monthly and sham every other month]) at 24 months. Feature-specific area analysis was conducted by Early Treatment Diabetic Retinopathy Study (ETDRS) regions of interest (ie, foveal, parafoveal, and perifoveal).
RESULTS
Among 936 participants, the mean (SD) age was 78.5 (7.22) years, and 570 participants (60.9%) were female. Pegcetacoplan, but not sham treatment, was associated with reduced growth rates of SD-OCT biomarkers for GA for up to 24 months. Reductions vs sham in least squares mean (SE) change from baseline of retinal pigment epithelium and outer retinal atrophy area were detectable at every time point from 3 through 24 months (least squares mean difference vs pooled sham at month 24, pegcetacoplan monthly: -0.86 mm2; 95% CI, -1.15 to -0.57; P < .001; pegcetacoplan every other month: -0.69 mm2; 95% CI, -0.98 to -0.39; P < .001). This association was more pronounced with more frequent dosing (pegcetacoplan monthly vs pegcetacoplan every other month at month 24: -0.17 mm2; 95% CI, -0.43 to 0.08; P = .17). Stronger associations were observed in the parafoveal and perifoveal regions for both pegcetacoplan monthly and pegcetacoplan every other month.
CONCLUSIONS AND RELEVANCE
These findings offer additional insight into the potential effects of pegcetacoplan on the development of GA, including potential effects on the retinal pigment epithelium and photoreceptors.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT03525600 and NCT03525613.
Topics: Humans; Geographic Atrophy; Tomography, Optical Coherence; Female; Intravitreal Injections; Male; Aged; Double-Blind Method; Visual Acuity; Fluorescein Angiography; Retinal Pigment Epithelium; Aged, 80 and over; Vascular Endothelial Growth Factor A; Fundus Oculi; Consensus; Treatment Outcome; Follow-Up Studies; Angiogenesis Inhibitors
PubMed: 38722644
DOI: 10.1001/jamaophthalmol.2024.1269 -
Quantitative Imaging in Medicine and... May 2024Image-based assessment of prostate cancer (PCa) is increasingly emphasized in the diagnostic workflow for selecting biopsy targets and possibly predicting clinically...
BACKGROUND
Image-based assessment of prostate cancer (PCa) is increasingly emphasized in the diagnostic workflow for selecting biopsy targets and possibly predicting clinically significant prostate cancer (csPCa). Assessment is based on Prostate Imaging-Reporting and Data System (PI-RADS) which is largely dependent on T2-weighted image (T2WI) and diffusion weighted image (DWI). This study aims to determine whether deep learning reconstruction (DLR) can improve the image quality of DWI and affect the assessment of PI-RADS ≥4 in patients with PCa.
METHODS
In this retrospective study, 3.0T post-biopsy prostate magnetic resonance imaging (MRI) of 70 patients with PCa in Korea University Ansan Hospital from November 2021 to July 2022 was reconstructed with and without using DLR. Four DWI image sets were made: (I) conventional DWI (CDWI): DWI with acceleration factor 2 and conventional parallel imaging reconstruction, (II) DL1: DWI with acceleration factor 2 using DLR, (III) DL2: DWI with acceleration factor 3 using DLR, and (IV) DL3: DWI with acceleration factor 3 and half average b-value using DLR. Apparent diffusion coefficient (ADC) value, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured by one reviewer, while two reviewers independently assessed overall image quality, noise, and lesion conspicuity using a four-point visual scoring system from each DWI image set. Two reviewers also performed PI-RADSv2.1 scoring on lesions suspected of malignancy.
RESULTS
A total of 70 patients (mean age, 70.8±9.7 years) were analyzed. The image acquisition time was 4:46 min for CDWI and DL1, 3:40 min for DL2, and 2:00 min for DL3. DL1 and DL2 images resulted in better lesion conspicuity compared to CDWI images assessed by both readers (P<0.05). DLR resulted in a significant increase in SNR, from 38.4±14.7 in CDWI to 56.9±21.0 in DL1. CNR increased from 25.1±11.5 in CDWI to 43.1±17.8 in DL1 (P<0.001). PI-RADS v2.1 scoring for PCa lesions was more agreeable with the DL1 reconstruction method than with CDWI (κ value CDWI, DL1; 0.40, 0.61, respectively). A statistically significant number of lesions were upgraded from PI-RADS <4 in CDWI image to PI-RADS ≥4 in DL1 images for both readers (P<0.05). Most of the PI-RADS upgraded lesions were from higher than unfavorable intermediate-risk groups according to the 2023 National Comprehensive Cancer Network guidelines with statistically significant difference of marginal probability in DL1 and DL2 for both readers (P<0.05).
CONCLUSIONS
DLR in DWI for PCa can provide options for improving image quality with a significant impact on PI-RADS evaluation or about a 23% reduction in acquisition time without compromising image quality.
PubMed: 38720859
DOI: 10.21037/qims-23-1379 -
Clinical and Translational Science May 2024No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and... (Review)
Review
No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and primary end points (PEs) of phase II and III trials intended to modify the natural course of the disease in patients with RMS. The purpose of the study is to explore trends/topics and discussion points in clinical trial design and PE, comparing them to regulatory guidelines and expert recommendations. Three trial registration systems, ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, were used and 60 trials were evaluated. The dominant clinical trial design was a randomized controlled parallel-arms trial and other details were as follows: in adult phase III confirmatory trials (n = 32), active-controlled double-blind trial (DBT) (53%) and active-controlled open-label assessor-masking trial (16%); in adult phase II dose-finding trials (n = 9), placebo- and active-controlled DBT (44%), placebo-controlled DBT (22%), and placebo-controlled add-on DBT (22%); and in pediatric phase III confirmatory trials (n = 8), active-controlled DBT (38%) and active-controlled open-label non-masking trial (25%). The most common PEs were as follows: in adult confirmatory trials, annual relapse rate (ARR) (56%) and no evidence of disease activity-3 (NEDA-3) (13%); in adult dose-finding trials, the cumulative number of T1 gadolinium-enhancing lesions (56%), combined unique active lesions (22%), and overall disability response score (22%); and in pediatric confirmatory trials, ARR (38%) and time to first relapse (25%). It was suggested that some parts of the regulatory guidelines and expert recommendations need to be revised.
Topics: Humans; Clinical Trials, Phase III as Topic; Clinical Trials, Phase II as Topic; Adult; Multiple Sclerosis, Relapsing-Remitting; Child; Research Design; Endpoint Determination; Randomized Controlled Trials as Topic
PubMed: 38708586
DOI: 10.1111/cts.13794 -
Translational Oncology Jul 2024Breast cancer is the most common female cancer globally. The method of choice for screening and diagnosing breast cancer is mammography, which is not widely available in...
BACKGROUND
Breast cancer is the most common female cancer globally. The method of choice for screening and diagnosing breast cancer is mammography, which is not widely available in Ghana as compared to ultrasonography. This study aimed to evaluate the sonographic features of solid breast lesions using the new sonographic Breast Imaging- Reporting and Data System (BI-RADS-US) lexicon for malignancy with histopathology as the gold standard.
METHODS
This was a prospective quantitative study that sonographically scanned female patients with breast masses and consecutively selected cases recommended for core biopsy from May 2018 to May 2021. Sixty (60) solid breast masses were described using the sonographic BI-RADS lexicon features. Lesion description and biopsy results from histopathology were compared and analyzed using Pearson's Chi-square test. Odds ratios, sensitivity, specificity, and predictive values were also calculated. Statistical significance level was set at p ≤ 0.05.
RESULTS
Irregular shape (p < 0.0001), spiculated mass margins (p < 0.0001), and not parallel mass orientation (p= 0.0007) were more commonly associated with malignant masses. The sensitivity of breast ultrasound for malignancy was 93.9 % and the specificity was 55.6 % with an overall accuracy rate of 76.6 %. The negative predictive value was 88.7 % and the positive predictive value was 72.1 %. Descriptors like irregular shape, non-parallel orientation, angular and spiculated margins, echogenic halo, and markedly hypoechoic internal content, demonstrated higher odds ratios for malignancy.
CONCLUSIONS
This study adds valuable insights to the diagnosis of breast cancer using the sonographic BI-RADS lexicon features. The results demonstrate that specific sonographic descriptors can effectively differentiate between benign and malignant breast masses.
PubMed: 38697004
DOI: 10.1016/j.tranon.2024.101976 -
Surgical Case Reports May 2024Accessory scrotum is a congenital scrotal anomaly that is usually located anterior to the anus and frequently presents with a lipoma in a bead-like shape. Herein, we...
BACKGROUND
Accessory scrotum is a congenital scrotal anomaly that is usually located anterior to the anus and frequently presents with a lipoma in a bead-like shape. Herein, we present an unusual case of an accessory scrotum with a lipoma connected by a narrow stalk and located posterior to the anus.
CASE PRESENTATION
A 1-month-old boy was referred to our hospital for a perineal mass present at birth. He was born at 37 weeks and 2 days, with a birth weight of 2962 g. No abnormalities occurred during the perinatal period, and the birth was uneventful. The mass had an unusual shape, comprising two masses connected by a narrow stalk. The base of the mass was posterior to the anus and was connected to the rectal mucosa. The proximal mass was elastic and soft without skinfolds, whereas the distal mass was elastic and soft with a scrotum-like skinfolds. Magnetic resonance imaging showed no spina bifida. High-intensity adipose tissues in both masses and low-intensity vessels or fibrous stroma in cord-like structures between the two masses were found on T2-weighted images. At 3 months of age, the patient underwent resection in the prone jackknife position. No tumorous lesions were connected to the mass on the rectal and coccyx sides, and the mass was completely removed, preserving the anal sphincter. Histologically, the distal mass had characteristics of a scrotum, whereas the proximal mass was exclusively a lipoma. The connecting stalk had normal skin structures and a blood vessel with parallel-running nerve bundles. The postoperative course was uneventful, and the patient was discharged on postoperative day 6.
CONCLUSIONS
This case of accessory scrotum was unusual in its location and the presence of a stalk connecting the accessory scrotum and lipoma. The mechanism underlying accessory scrotum development remains unclear, and our report may impact the discourse regarding the embryological development of the accessory scrotum.
PubMed: 38691310
DOI: 10.1186/s40792-024-01906-w -
BMC Oral Health Apr 2024Dentin hypersensitivity, often occurring after dental treatments or from erosive lesions, is a prevalent patient complaint. This study introduces a paste combining 8%... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Evaluation and comparison of the effects of a new paste containing 8% L-Arginine and CaCO3 plus KNO3 on dentinal tubules occlusion and dental sensitivity: a randomized, triple blinded clinical trial study.
BACKGROUND
Dentin hypersensitivity, often occurring after dental treatments or from erosive lesions, is a prevalent patient complaint. This study introduces a paste combining 8% L-arginine, calcium carbonate, and potassium nitrate to evaluate its impact on dentinal tubules occlusion, dentin permeability, and tooth sensitivity.
METHODS
Dentin surfaces from 24 third molars (thickness: 2 mm) were divided into two groups of 12. One received the experimental paste, while the other received a placebo without desensitizer. Permeability and sealing ability were assessed through scanning electron microscopy (SEM) and dentin permeability measurement. The pastes' effects on hypersensitivity were then examined in a triple-blind, randomized parallel-armed clinical trial with 16 eligible patients. Sensitivity to cold, touch, and spontaneous stimuli was recorded using the VAS scale at various intervals post-treatment. Statistical analysis was conducted using Shapiro-Wilk, Mann-Whitney U, Friedman, and Wilcoxon tests (α = 0.05).
RESULTS
The permeability test demonstrated a significant reduction in dentin permeability in the experimental group (P = 0.002) compared to the control (P = 0.178). SEM images revealed most dentinal tubules in the intervention samples to be occluded. Clinically, both groups showed a significant decrease in the three types of evaluated sensitivity throughout the study. However, no significant difference in sensitivities between the two groups was observed, with the exception of cold sensitivity at three months post-treatment (P = 0.054).
CONCLUSION
The innovative desensitizing paste featuring 8% L-arginine, calcium carbonate, and potassium nitrate effectively occluded dentinal tubules and reduced dentin permeability. It mitigated immediate and prolonged dentin hypersensitivity to various stimuli, supporting its potential role in managing dentin hypersensitivity.
TRIAL REGISTRATION
http://irct.ir : IRCT20220829055822N1, September 9th, 2022.
Topics: Humans; Dentin Sensitivity; Arginine; Calcium Carbonate; Nitrates; Male; Female; Potassium Compounds; Dentin Desensitizing Agents; Adult; Microscopy, Electron, Scanning; Dentin Permeability; Dentin; Toothpastes; Young Adult; Middle Aged
PubMed: 38685035
DOI: 10.1186/s12903-024-04298-3