Search Results (63)

Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a median overall survival (OS) of just 10–16 months. Although recent advances in systemic therapies, including small molecule inhibitors, monoclonal antibodies, chemotherapeutics, and gene therapies, have demonstrated success in other malignancies, their effectiveness in central nervous system (CNS) cancers is significantly limited by poor blood–brain barrier (BBB) permeability and subtherapeutic drug concentrations in the brain. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these limitations by enhancing CNS drug penetration and selectively targeting metastatic brain tumor cells while minimizing off-target effects. This review summarizes recent preclinical and clinical developments in nanoparticle-based therapies for BM. It is evident from these studies that NPs can carry with them a range of therapeutics, including chemotherapy, immunotherapy, small molecule inhibitors, gene therapies, radiosensitizers, and modulators of tumor microenvironment to the BM. Moreover, preclinical studies have shown encouraging efficacy in murine models, highlighting the potential of these platforms to improve therapeutic outcomes. However, clinical translation remains limited, with few ongoing trials. To close this translational gap, future work must address clinical challenges such as trial design, regulatory hurdles, and variability in BBB permeability while developing personalized nanoparticle-based therapies tailored to individual tumor characteristics. Full article

The unique microbial communities present on fruit surfaces significantly influence the fermentation process and product quality of artisanal cider production, constituting a microbial terroir analogous to that recognized in viticulture. In this study, we investigated the microbial composition and diversity associated with the apple varietals (Empire, Golden Delicious, and Idared) cultivated by two different orchard producers in the Hudson River Valley of New York. Using 16S rRNA and ITS amplicon sequencing, we identified distinct bacterial and fungal communities that varied significantly according to the apple varietal and orchard location. Notably, the orchard was the dominant factor shaping both the bacterial and fungal communities on the apples’ surfaces, with the varietal differences also playing a significant, albeit secondary, role. For example, we found that the bacterial genera Acidophilim sp. and 1174-901-12 sp., as well as the fungus Sporobolmyces patagonicus, were important markers of the orchard in which the apples were cultivated. These microbial signatures persisted into the early stages of cider fermentation, suggesting their potential influence on the cider quality and flavor profile. Our findings underscore the critical importance of the microbial terroir in cider production, and suggest that targeted management practices can leverage regional microbial diversity to enhance the distinctiveness and marketability of artisanal cider products. Full article

Background: The management of rare tumors at reference centers with specialized multidisciplinary tumor boards (MTBs) improves patient survival. No international standardized diagnostic and treatment recommendations for pediatric patients with adrenocortical carcinoma (ACC) exist so far. The aim of this case-based study is to determine how congruent treatment recommendations are in different specialized institutions in different countries. Methods: In this cross-sectional, case-based survey study, five anonymized patient cases, including imaging data of pediatric adrenocortical carcinomas (pACCs), were distributed to seven international specialized centers located in Brazil, Germany, India, Italy, Poland, Turkey, and the USA. The centers were tasked with providing recommendations regarding the treatment sequence and modalities, as well as indicating the level of consensus on these decisions within their MTBs. For each case, the treatment approach recommended by the highest number of centers was recorded to calculate an agreement percentage relative to all treatment recommendations made. The consensus level for each case was determined on a scale of 1 to 10, with higher scores indicating greater agreement among MTB members. Results: A total of five patient cases were discussed across seven MTBs, yielding a total of 34 treatment recommendations. The agreement percentages for the primary therapeutic approach for each case were as follows: primary therapeutic approach: 88.6%; surgical approaches: 51.8%; and systemic chemotherapy recommendations: 53%. Conclusions: This study represents the first case-based analysis of international inter-center agreement on pediatric ACC management. Inter-center agreement regarding treatment allocation and sequencing was low, while the level of consensus within each MTB was high. These findings point to potentially significant and clinically relevant differences in treatment standards across centers, highlighting the need for international collaboration and standardized diagnostic and therapeutic recommendations, especially for rare tumors. Increased case-based exchanges between centers are essential to reduce the substantial discrepancies observed here and to further standardize the management of pediatric patients with ACC. Full article

Chest wall perforator flaps (CWPFs) are a promising option for partial breast reconstruction but are underutilized, particularly in resource-limited settings. This retrospective observational study explores the feasibility and impact of CWPFs in breast-conserving surgery at our single-surgeon center, where 203 procedures were performed between 2018 and 2023. We evaluate 200 cases treated after multidisciplinary tumor board discussions and shared decision-making, assessing clinicopathological data, surgical outcomes, oncological results, cosmetic outcomes, and patient-reported outcome measures (PROMs). The median age of patients was 52.5 years. Single CWPFs were used in 75.9% and dual flaps in 24.1%. Sentinel node biopsy was performed in 76.9% of malignant cases, with no positive margins. Minor complications occurred in 11%, and no major complications were reported. At a 27-month median follow-up, the overall survival rate was 97.5%, with a disease-free survival of 92.1%. Cosmetic outcomes were good-to-excellent, and PROMs indicated high satisfaction. This largest single-surgeon study from Asia demonstrates the transformative role of CWPFs in breast conservation surgery for Indian women with sizable, locally advanced tumors. The technique offers excellent oncological and cosmetic outcomes, reduced costs, and a shorter operative time, highlighting the need for oncoplastic algorithms in resource-limited settings to improve breast conservation accessibility. Full article

Background: Lower socioeconomic status (SES) has been associated with increased mortality from coronary heart disease. This excess risk, relative to affluent patients, may be due to a combination of more adverse cardiovascular-risk factors, inequalities in access to cardiac investigations, longer waiting times for cardiac revascularisation and lower use of secondary prevention drugs. We sought to investigate whether socio-economic status influenced long-term all-cause mortality after PCI in a large metropolitan city (London), which serves a population of 11 million people with a mixed social background over a 10-year period. Methods: We conducted an observational cohort study of 123,780 consecutive PCI procedures from the Pan-London (United Kingdom) PCI registry. This data set is collected prospectively and includes all patients treated between January 2005 and December 2015. The database includes PCI performed for stable angina and ACS (ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina). Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0–5.1) years and the primary outcome was all-cause mortality. Results: The mean age of the patients was 64.3 ± 12.1 years and 25.2% were female. A total of 22.4% of patients were diabetic and 27.3% had a history of previous myocardial infarction. The rates of long-term all-cause mortality increased progressively across quintiles of IMD score, with patients in Q5 showing significantly higher long-term mortality rates compared with patients in Q1 (p = 0.0044). This persisted following the inclusion of a propensity score in the proportional hazard model as a covariate (HR for Q5 compared to Q1: 1.15 [95% CI: 1.10–1.42]). Conclusions: This study has demonstrated that low SES is an independent predictor of adverse clinical outcomes following PCI in the large, diverse metropolitan city of London. There clearly are inequalities in cardio-vascular risk factors, time to access to medical treatment/PCI, access to complex imaging and devices during PCI, access to secondary prevention after PCI, and even race differences. Hence, attention to reducing the burden of cardiovascular risk factors and improving primary prevention, particularly in patients with lower SES, is required. Full article

Glioblastomas are the most common primary malignant brain tumor. Most of the recent improvements their treatment are due to improvements in surgery. Although many would consider surgery as the most personalized treatment, the variation in resection between surgeons suggests there remains a need for objective measures to determine the best surgical treatment for individualizing therapy for glioblastoma. We propose applying a personalized medicine approach to improve outcomes for patients. We suggest looking at personalizing preoperative preparation, improving the resection target by understanding what needs removing and what ca not be removed, and better patient selection with personalized rehabilitation plans for all patients. Full article

Mitochondrial genomes serve as essential tools in evolutionary biology, phylogenetics, and population genetics due to their maternal inheritance, lack of recombination, and conserved structure. Traditional morphological methods for identifying nematodes are often insufficient for distinguishing cryptic species complexes. This study highlights recent advancements in nematode mitochondrial genome research, particularly the impact of long-read sequencing technologies such as Oxford Nanopore. These technologies have facilitated the assembly of mitochondrial genomes from mixed soil samples, overcoming challenges associated with designing specific primers for long PCR amplification across different groups of parasitic nematodes. In this study, we successfully recovered and assembled eleven nematode mitochondrial genomes using long-read sequencing, including those of two plant-parasitic nematode species. Notably, we detected Heterodera cruciferae in Victoria, expanding its known geographic range within Australia. Additionally, short-read sequencing data from a previous draft genome study revealed the presence of the mitochondrial genome of Heterodera filipjevi. Comparative analyses of Heterodera mitogenomes revealed conserved protein-coding genes essential for oxidative phosphorylation, as well as gene rearrangements and variations in transfer RNA placement, which may reflect adaptations to parasitic lifestyles. The consistently high A+T content and strand asymmetry observed across species align with trends reported in related genera. This study demonstrates the utility of long-read sequencing for identifying coexisting nematode species in agricultural fields, providing a rapid, accurate, and comprehensive alternative to traditional diagnostic methods. By incorporating non-target endemic species into public databases, this approach enhances biodiversity records and informs biosecurity strategies. These findings reinforce the potential of mitochondrial genomics to strengthen Australia’s as well as the global biosecurity framework against plant-parasitic nematode threats. Full article

Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the smallest of the three, a 23 kb duplication on chromosome 4 (hg38|4:25,554,985-25,578,843). Methods: Using CRISPR and bridging oligos, we introduced the duplication into the Kolf2.1J iPSC line. We differentiated the parent line and the line with the duplication into cortical neurons using a three-dimensional differentiation protocol, and performed bulk RNASeq on neural progenitors (day 14) and differentiated neurons (day 63). Results: We successfully introduced the duplication into Kolf2.1J iPSCs by nucleofecting a bridging oligo for the newly formed junction along with cas9 ribonucleoparticles. We confirmed that the cells had a tandem duplication without inversion or deletion. The parent line and the line with the duplication both differentiated into neurons reliably. There were a total of 37 differentially expressed genes (DEGs) at day 63, 25 downregulated and 12 upregulated. There were 55 DEGs at day 14, 18 of which were also DEGs at day 63. The DEGs included a number of protocadherins, several genes involved in neuronal development, including SLITRK2, CSMD1, and VGF, and several genes of unknown function. Conclusions: A copy number variant (CNV) that confers risk for strabismus affects gene expression of several genes involved in neural development, highlighting that strabismus most likely results from abnormal neural development, and identifying several new genes and pathways for further research into the pathophysiology of strabismus. Full article

Synbiotics are mixtures of prebiotics and probiotics that enhance the activity of probiotic bacteria when co-administered to provide greater benefits to the host. Traditionally, the synbiotics that have been discovered enhance gut probiotic strains and are nutritionally complex molecules that survive digestive breakdown until they reach the later stages of the intestinal tract. Here, we screened and identified sugars or sugar substitutes as synbiotics for the oral probiotic strains Streptococcus salivarius BLIS K12 and BLIS M18. Using a modified deferred antagonism assay, we found that 0.5% (w/v) galactose and 2.5% (w/v) raffinose were the best candidates for use as synbiotics with BLIS K12 and M18, as they trigger enhanced antimicrobial activity against a range of bacteria representing species from the mouth, gut, and skin. Using reverse transcriptase quantitative PCR, we found that this enhanced antimicrobial activity was caused by the upregulation of the lantibiotic genes salA, salB, and sal9 in either K12 or M18. This led to the conclusion that either 2.5% (w/v) raffinose or 0.5% (w/v) galactose, respectively, are suitable synbiotics for use in conjunction with BLIS K12 and M18 to enhance probiotic performance. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous system. HAM/TSP individuals exhibit CD4+ and CD8+ T cells with elevated co-expression of multiple inhibitory immune checkpoint proteins (ICPs), but ICP blockade strategies can only partially restore CD8+ T-cell effector function. Exosomes, small extracellular vesicles, can enhance the spread of viral infections and blunt anti-viral responses. Here, we evaluated the impact of exosomes isolated from HTLV-1-infected cells and HAM/TSP patient sera on dendritic cell (DC) and T-cell phenotypes and function. We observed that exosomes derived from HTLV-infected cell lines (OSP2) elicit proinflammatory cytokine responses in DCs, promote helper CD4+ T-cell polarization, and suppress CD8+ T-cell effector function. Furthermore, exosomes from individuals with HAM/TSP stimulate CD4+ T-cell polarization, marked by increased Th1 and regulatory T-cell differentiation. We conclude that exosomes in the setting of HAM/TSP are detrimental to DC and T-cell function and may contribute to the progression of pathology with HTLV-1 infection. Full article

Background: Audiological diagnosis and rehabilitation often involve the assessment of whether the maximum speech identification score (PB_max) is poorer than expected from the pure-tone average (PTA) threshold. This requires the estimation of the lower boundary of the PB_max values expected for a given PTA (one-tailed 95% confidence limit, CL). This study compares the accuracy and consistency of three methods for estimating the 95% CL. Method: The 95% CL values were estimated using a simulation method, the Harrell–Davis (HD) estimator, and non-linear quantile regression (nQR); the latter two are both distribution-free methods. The first two methods require the formation of sub-groups with different PTAs. Accuracy and consistency in the estimation of the 95% CL were assessed by applying each method to many random samples of 50% of the available data and using the fitted parameters to predict the data for the remaining 50%. Study sample: A total of 642 participants aged 17 to 84 years with sensorineural hearing loss were recruited from audiology clinics. Pure-tone audiograms were obtained and PB_max scores were measured using monosyllables at 40 dB above the speech recognition threshold or at the most comfortable level. Results: For the simulation method, 6.7 to 8.2% of the PB_max values fell below the 95% CL for both ears, exceeding the target value of 5%. For the HD and nQR methods, the PB_max values fell below the estimated 95% CL for approximately 5% of the ears, indicating good accuracy. Consistency, estimated from the standard deviation of the deviations from the target value of 5%, was similar for all the methods. Conclusions: The nQR method is recommended because it has good accuracy and consistency, and it does not require the formation of arbitrary PTA sub-groups. Full article

Glioblastoma multiforme (GBM) is a glioma and the most aggressive type of brain tumor with a dismal average survival time, despite the standard of care. One promising alternative therapy is boron neutron capture therapy (BNCT), which is a noninvasive therapy for treating locally invasive malignant tumors, such as glioma. BNCT involves boron-10 isotope capturing neutrons to form boron-11, which then releases radiation directly into tumor cells with minimal damage to healthy tissues. This therapy lacks clinically approved targeted blood–brain-barrier-permeating delivery vehicles for the central nervous system (CNS) entry of therapeutic boron-10. Gold nanoparticles (GNPs) are selective and effective drug-delivery vehicles because of their desirable properties, facile synthesis, and biocompatibility. This review discusses biomedical/therapeutic applications of GNPs as a drug delivery vehicle, with an emphasis on their potential for carrying therapeutic drugs, imaging agents, and GBM-targeting antibodies/peptides for treating glioma. The constraints of GNP therapeutic efficacy and biosafety are discussed. Full article

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored. Full article

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in ACVRL1 (encoding activin receptor-like kinase 1 [ALK1]), ENG (encoding endoglin [CD105]), or SMAD4. In a consecutive single-centre series of 37 positive clinical genetic tests performed in 2021–2023, a skewed distribution pattern was noted, with 30 of 32 variants reported only once, but ACVRL1 c.1231C>T (p.Arg411Trp) identified as the disease-causal gene in five different HHT families. In the same centre’s non-overlapping 1992–2020 series where 110/134 (82.1%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was identified in nine further families. In a 14-country, four-continent HHT Mutation Database where 181/250 (72.4%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was reported by 12 different laboratories, the adjacent ACVRL1 c.1232G>A (p.Arg411Gln) by 14, and ACVRL1 c.1120C>T (p.Arg374Trp) by 18. Unlike the majority of HHT-causal ACVRL1 variants, these encode ALK1 protein that reaches the endothelial cell surface but fails to signal. Six variants of this type were present in the three series and were reported 6.8–25.5 (mean 8.9) times more frequently than the other ACVRL1 missense variants (all p-values < 0.0039). Noting lower rates of myocardial infarction reported in HHT, we explore potential mechanisms, including a selective paradigm relevant to ALK1′s role in the initiating event of atherosclerosis, where a plausible dominant negative effect of these specific variants can be proposed. In conclusion, there is an ~9-fold excess of kinase-inactive, cell surface-expressed ACVRL1/ALK1 pathogenic missense variants in HHT. The findings support further examination of differential clinical and cellular phenotypes by HHT causal gene molecular subtypes. Full article