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Aim: The aim of this study was to evaluate the molecular mechanisms of Lactobacillus strains in improving ageing of the musculoskeletal system. Methods and Results: The anti‐ageing mechanism of three probiotics strains Lactobacillus fermentum DR9, Lactobacillus paracasei OFS 0291 and L. helveticus OFS 1515 were evaluated on gastrocnemius muscle and tibia of d‐galactose‐induced ageing rats. Upon senescence induction, aged rats demonstrated reduced antioxidative genes CAT and SOD expression in both bone and muscle compared to the young rats (P < 0·05). Strain L. fermentum DR9 demonstrated improved expression of SOD in bone and muscle compared to the aged rats (P < 0·05). In the evaluation of myogenesis‐related genes, L. paracasei OFS 0291 and L. fermentum DR9 increased the mRNA expression of IGF‐1; L. helveticus OFS 1515 and L. fermentum DR9 reduced the expression of MyoD, in contrast to the aged controls (P < 0·05). Protective effects of L. fermentum DR9 on ageing muscle were believed to be contributed by increased AMPK‐α2 expression. Among the osteoclastogenesis genes studied, TNF‐α expression was highly elevated in tibia of aged rats, while all three probiotics strains ameliorated the expression. Lactobacillus fermentum DR9 also reduced the expression of IL‐6 and TRAP in tibia when compared to the aged rats (P < 0·05). All probiotics treatment resulted in declined proinflammatory cytokines IL‐1β in muscle and bone. Conclusions: Lactobacillus fermentum DR9 appeared to be the strongest strain in modulation of musculoskeletal health during ageing. Significance and Impact of the Study: The study demonstrated the protective effects of the bacteria on muscle and bone through antioxidative and anti‐inflammatory actions. Therefore, L. fermentum DR9 may serve as a promising targeted anti‐ageing therapy. [ABSTRACT FROM AUTHOR]

Overall survival is improved in glioblastoma (GBM) by multimodality therapy including surgical resection and adjuvant radiation (RT). In primary GBM (pGBM), a classic problem is the delineation of the infiltrating microscopic tumor margin for focal therapies. In recurrent GBM (rGBM), the imaging is further confounded by changes from the pGBM treatments. As a result, rGBM is often not given RT due to confusing imaging or delivered with a tiny clinical target volume (CTV) that is likely missing high-risk non-enhancing tumor due to fears about re-RT radiation necrosis. Whole-brain spectroscopic MRI (sMRI) is an emerging MRI technique with similar resolution to brain PET that can detect native metabolites and has been applied to define CTV in pGBM. We wished to determine whether it may also have usefulness in defining the CTV for rGBM. Patients with pGBM (n=21) and rGBM (n=21) were prospectively consented for sMRI. T1-post contrast (T1PC) and T2/FLAIR MRI volumes were contoured. sMRIs were used to generate relative choline:N-acetylaspartate>2 (rCN>2) maps normalized to contralateral normal appearing white matter, which have been validated to correlate strongly with the presence of occult tumor invasion. sMRI-defined volumes were contoured using the rCN>2 maps. Hausdorff distances were calculated to define the margin necessary to cover rCN>2 in both pGBM and rGBM. In rGBM, mock CTV expansions from the T1PC volume were created to determine non-selective CTV expansions needed to cover occult tumor invasion. For pGBM, the mean T1PC volume was 49.9 cc, mean T2/FLAIR volume was 108.5 cc, and mean rCN>2 was 72.5 cc. For rGBM, the mean T1PC volume was 28.6 cc, mean T2/FLAIR volume was 140.7 cc, and mean rCN>2 was 51.8 cc. The ratio of T1PC to T2/FLAIR volumes was 0.53 in pGBM and 0.25 in rGBM (p<0.001). The mean Hausdorff distance indicating the maximum additional distance between T1PC and rCN>2 was 22.9 mm in pGBM and 28.3 mm in rGBM. Our findings support ∼2 cm expansions in pGBM as per clinical standards. But, in rGBM, no CTV expansion from the T1PC volume (i.e., per RTOG 1205 trial protocol) resulted in only 54% of total disease coverage. With 10-, 15- and 20-mm CTV expansions from the T1PC volume, 94%, 98%, and 99% of total disease was covered, respectively. sMRIs rCN>2 maps define occult disease in both pGBM and rGBM. These volumes extend approximately 2-3 cm beyond the disease seen on T1PC MRI. In rGBM, CTV expansions based on rCN>2 maps could allow for increased coverage of occult disease typically missed with standard radiation therapy volumes. [ABSTRACT FROM AUTHOR]

Contrast MRI after chemoradiotherapy (chemoRT) shows areas of possible tumor growth in ∼50% of glioblastoma patients compared to pre-RT, but changes during chemoRT are rarely investigated due to logistics of frequent standalone MRI. Daily MRI is feasible with MRI-linac, but the frequency of gadolinium contrast imaging for adaptive RT remains undefined. To identify the need for contrast during chemoRT, we analyzed findings on MRI-linac T2-weighted (T2) MRI and compared those to standalone T1-post contrast (T1+C) and T2 MRI. Using an IRB-approved prospective cohort of glioblastoma patients undergoing 30 fractions of chemoRT to 60 Gy, standalone MRIs (1.5 or 3T) at 3 timepoints: 1) 1 week pre-RT, 2) mid-RT (end of week 4/beginning of week 5 of treatment) when available, and 3) 1-month post-RT, were compared with T2 treatment set-up scans on 0.35T MRI-linac. Two regions of interest (ROI) were contoured: 1) lesion and 2) cavity (post-surgical resection cavity). Lesion was defined as tumor and edema on T2 MRI, and as enhancing disease on T1+C MRI. ROI volumes from MRI-linac and standalone MRI acquired on the same day were compared using linear fits. Percent change from pre- to post-treatment was calculated for lesion. Thirty-five patients that underwent RT on MRI-linac were analyzed. Defined on the MRI-linac pre-RT T2 planning scan, 8 patients had visible cavity only, 15 had a mix of both cavity and lesion, and 12 had lesion only (n=23 for cavity, n=27 for lesion). R2 values for linear fits between standalone MRI vs. MRI-linac can be seen in the table (n=number of comparisons included in model). There was a moderate correlation between T1+C and MRI-linac lesion, despite MRI-linac T2's inability to separate contrast enhancement from surrounding non-enhancing tumor and edema. From pre- to post-treatment, standalone T1+C and MRI-linac T2 lesions changed together – shrank (n=7) or grew (n=11) – in 18 (51%) patients. Another 9 patients (26%) had growth on MRI-linac T2 while the T1+C component shrank. In no patient did T1+C lesion grow while the MRI-linac T2 shrank. No patients with cavity only on MRI-linac (n=8, 23%) had any lesion growth on T1+C from pre- to post-treatment. Daily low-field MRI-linac non-contrast imaging demonstrates changes in resection cavity and tumor/edema during chemoRT. We found that these changes can be used as a signal for when to consider IV contrast for adaptive MRI-RT in glioblastoma. If T1+C volumes are desired for adaptation, a selective approach can be employed where MRI-linac T2/non-contrast lesion growth (n=20, 57%) can be used to trigger contrast injection at selected timepoints. In patients with no lesion growth on non-contrast imaging/MRI-linac (n=15, 43%), contrast administration may not be needed. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) by an MRI-linear accelerator (Linac) enables daily MRI for glioblastoma (GBM) RT adaptation. Multiparametric MRI (mpMRI) may further enhance adaptive RT decisions using physiologic tumor changes reflected in quantitative imaging. This abstract analyzes the ability of T1, T2, and T2* relaxometry to serve as predictors for early GBM progression. The purpose of our study was to discover how multiparametric MRI values change during RT and compare them to patient outcomes. 29 patients (11 Female; median age of 64) with newly diagnosed GBM underwent chemoradiation on a 0.35 T MRI-Linac with 60 Gy in 30 fractions and temozolomide. IRB-approved research imaging was acquired on alternate days of treatment with a scanning protocol including Strategically Acquired Gradient Echo (STAGE: TR = 42 ms; TE = 5/20.63/34.14 ms; Voxel size = 1.5×1.5×4mm; FA = 10/50°) and multi-echo T2 (TR = 4000 ms; TE = 29/73/131 ms; Voxel size = 1.6×1.6×6 mm) sequences. T1, PD (Proton Density), T2*, and T2 maps were generated using developed code. Map values within region of interest (ROI) (Lesion/Cavity on balanced Steady State Free Precession image +1 cm and excluding the resection cavity) were calculated. Parametric response maps (PRM) were defined as voxel-by-voxel percent change between every fraction and pre-RT by classifying each ROI voxel as either decreased >5 %, increased >5 % or unchanged (+/-5%). Patients were divided into 2 groups based on early clinical response to treatment: NP (no progression) and TP (true progression). Non-progressors included patients with pseudoprogression as well. Statistical analysis included analysis of variance of PRMs for every response group and stepwise multinominal logistical regression with two outcomes: NP and TP. Correlation with overall survival (OS) was evaluated by Cox proportional hazards models. The results were considered statistically significant at the two-sided 5% comparison-wise significance level. 18 patients (62 %) had NP and 11 (38 %) had TP. We observed a significant difference between non-progressors and true-progressors in voxels with increasing of T2 (NP: 40 ± 2.3 %; TP: 47 ± 3.7%, P = 0.02) and T2* values (NP: 8 ± 0.3 %; TP: 10 ± 0.5 %; P = 0.04) more than 30% on 1st and 2nd week of RT. The increasing of T2 and T2* values more than 30% at week 2 was correlated with OS (HR = 4 and 3.08, respectively, P < 0.05). Based on Akaike's information criteria, the significant predictors of response in the models were increasing of T2 and T2* values more than 30% (P < 0.001). mpMRI PRMs demonstrated significant differences mostly in T2* and T2 values in the 1st and 2nd weeks of RT in poorly responding GBMs. As such patients have the worst prognosis, they might benefit from early therapy intensification or adaptation with MRI-Linac and/or other therapies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a form of neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ), hyperphosphorylated Tau, and neuroinflammation. The increasing population affected by AD urges for the development of effective treatments. The correlation between AD and gut microbiome remains underexplored, potentially providing a better understanding of the disease. Salvianolic acid A (Sal A) and salvianolic acid B (Sal B) are the active components extracted from Salvia miltiorrhiza (Danshen), and their antioxidant, anti-inflammation and Aβ inhibition activities were shown previously. In this study, these compounds were used to investigate their effects on Aβ toxicity, using Drosophila melanogaster expressing human Aβ42 as the model organism, by examining their lifespan and changes in gut bacterial communities. The study used two batches of flies, reared on food with or without methylparaben (MP) supplementation to evaluate the influence of MP on this animal model during pharmacological studies. MP is a common antimicrobial agent used in flies' food. The treatment of Sal A prolonged the lifespan of Aβ-expressing flies reared on MP-supplemented food significantly (P < 0.001), but not those without MP. The lifespan of Sal B-treated flies did not show a significant difference compared to untreated flies for both groups reared on food with and without MP. Sal A-treated flies in the presence of MP exhibited a lower abundance of Corynebacterium and Enterococcus than the untreated flies, while Lactiplantibacillus was the most dominant taxa. Urea cycle was predicted to be predominant in this group compared to the untreated group. The control group, Aβ-expressing flies treated with Sal A and Sal B on MP-supplemented food had improved lifespan compared to their respective groups reared on food without MP, while untreated Aβ-expressing flies was the exception. The gut microbiota composition of flies reared on MP-supplemented food was also significantly different from those without MP (P < 0.001)., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Asia remains vulnerable to new and emerging infectious diseases. Understanding how to improve next generation sequencing (NGS) use in pathogen surveillance is an urgent priority for regional health security. Here we developed a pathogen genomic surveillance assessment framework to assess capacity in low-resource settings in South and Southeast Asia. Data collected between June 2022 and March 2023 from 42 institutions in 13 countries showed pathogen genomics capacity exists, but use is limited and under-resourced. All countries had NGS capacity and seven countries had strategic plans integrating pathogen genomics into wider surveillance efforts. Several pathogens were prioritized for human surveillance, but NGS application to environmental and human-animal interface surveillance was limited. Barriers to NGS implementation include reliance on external funding, supply chain challenges, trained personnel shortages and limited quality assurance mechanisms. Coordinated efforts are required to support national planning, address capacity gaps, enhance quality assurance and facilitate data sharing for decision making., (© 2024. The Author(s).)

Background: Although molecular biomarkers have significantly advanced precision oncology in glioblastoma, the prevalence of these biomarkers by race remains underexplored. This study aims to characterize the genomic alterations in glioblastoma across Asian, Black, and White patients, offering insights into racial disparities that may influence treatment outcomes and disease progression., Methods: Analyzing data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database V13.0, this study examined 2390 primary glioblastoma samples from unique patients. Genomic alterations in 566 cancer-related genes were assessed using targeted next-generation sequencing panels from 3 large cancer institutes. The patient cohort included 112 Asians, 67 Blacks, and 2211 Whites. Statistical significance of associations between genomic alterations and race was evaluated using the chi-squared test, with the Benjamini-Hochberg method applied to control for multiple testing adjustments., Results: Significant racial differences were observed in the frequency of genomic alterations. Asians exhibited a higher frequency of TP53 alterations (52.68%, P < 0.001), Blacks showed more frequent alterations in NRAS (7.46%, P < 0.001), MTOR (10.45%, P = 0.039), and TET2 (8.96%, P = 0.039), and Whites had a higher occurrence of PTEN alterations (48.67%, P = 0.045). Additionally, Black patients had an elevated rate of RET deletions (14.29%, P < 0.001)., Conclusions: This study identifies significant racial disparities in the alteration frequencies of 6 key glioblastoma genes: NRAS, TP53, MTOR, TET2, PTEN, and RET. These findings underscore the need for racial considerations in glioblastoma treatment strategies and highlight potential avenues for targeted therapeutic interventions. Further research is needed to explore the clinical implications of these genomic disparities., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The experience of patients with brain metastases treated with stereotactic radiosurgery (SRS) may shape attitudes towards salvage therapy. Furthermore, physician attitudes towards salvage therapy may differ based on specialty and experience. Our objective is to compare physician attitudes and patient experiences with SRS., Methods: Eligible patients with brain metastases treated with one course of SRS or fractionated stereotactic radiotherapy (FSRT) without whole brain radiotherapy (WBRT) in the definitive or postoperative setting at a single institution were surveyed from 11/2021 to 11/2022 regarding their perspectives on salvage therapy. A separate 11-question multi-disciplinary physician survey was distributed to residents, fellows and attendings at seven additional academic institutions in the US. Chi-square test and Mann-Whitney U test were used to assess differences., Results: A total of 30 patients and 88 physicians were surveyed. Most patients reported being satisfied or very satisfied with initial SRS/FSRT (90%). When given an option between WBRT or SRS for salvage treatment, all patients favored SRS. The physicians consisted of radiation oncologists (69.3%), neurosurgeons (19.3%), medical oncologists (8.0%), and neuro-oncologists (3.4%). Most physicians were confident or very confident in their ability to discuss the risks and benefits of SRS for brain metastases (78.9%), but this was significantly lower if the patient had received prior SRS (56.6%, P<.001). In these cases, there were significant differences in response by medical specialty and confidence level (P<0.05)., Conclusions: Patients and physicians view tumor control followed by long-term toxicity as the most important factors for salvage therapy after initial SRS for brain metastases., Competing Interests: This research was supported through funds provided by the University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center Department of Radiation Oncology. No external funding or grants were used for this work. Authors’ disclosure of potential conflicts of interest The authors have nothing to disclose., (© 2024 Old City Publishing, Inc.)

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aβ) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aβ42 is the most damaging and aggressively aggregating Aβ isomer produced in the brain. Although Aβ42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aβ42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aβ42 and for reducing fibrillary Aβ42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aβ42. Additionally, this compound diminished Aβ42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alzheimer's disease (AD) is the most common neurodegenerative condition in civilizations worldwide. The distinctive occurrence of amyloid-beta (Aβ) accumulation into insoluble fibrils is part of the disease pathophysiology with Aβ42 being the most toxic and aggressive Aβ species. The polyphenol, p-Coumaric acid (pCA), has been known to boost a number of therapeutic benefits. Here, pCA's potential to counteract the negative effects of Aβ42 was investigated. First, pCA was confirmed to reduce Aβ42 fibrillation using an in vitro activity assay. The compound was next examined on Aβ42-exposed PC12 neuronal cells and was found to significantly decrease Aβ42-induced cell mortality. pCA was then examined using an AD Drosophila melanogaster model. Feeding of pCA partially reversed the rough eye phenotype, significantly lengthened AD Drosophila's lifespan, and significantly enhanced the majority of the AD Drosophila's mobility in a sex-dependent manner. The findings of this study suggest that pCA may have therapeutic benefits for AD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common neurological ailment worldwide. Its process comprises the unique aggregation of extracellular senile plaques composed of amyloid-beta (Aβ) in the brain. Aβ42 is the most neurotoxic and aggressive of the Aβ42 isomers released in the brain. Despite much research on AD, the complete pathophysiology of this disease remains unknown. Technical and ethical constraints place limits on experiments utilizing human subjects. Thus, animal models were used to replicate human diseases. The Drosophila melanogaster is an excellent model for studying both physiological and behavioural aspects of human neurodegenerative illnesses. Here, the negative effects of Aβ42-expression on a Drosophila AD model were investigated through three behavioural assays followed by RNA-seq. The RNA-seq data was verified using qPCR. AD Drosophila expressing human Aβ42 exhibited degenerated eye structures, shortened lifespan, and declined mobility function compared to the wild-type Control. RNA-seq revealed 1496 genes that were differentially expressed from the Aβ42-expressing samples against the control. Among the pathways that were identified from the differentially expressed genes include carbon metabolism, oxidative phosphorylation, antimicrobial peptides, and longevity-regulating pathways. While AD is a complicated neurological condition whose aetiology is influenced by a number of factors, it is hoped that the current data will be sufficient to give a general picture of how Aβ42 influences the disease pathology. The discovery of molecular connections from the current Drosophila AD model offers fresh perspectives on the usage of this Drosophila which could aid in the discovery of new anti-AD medications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)