tbuckley/cabot-search huggingface dataset:
The role of endoplasmic reticulum–mitochondria-associated membranes in diabetic kidney disease
Authors: Ahmed Elwakiel, Akash Mathew, Berend Isermann
Journal: Cardiovascular Research (2023)

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The pathomechanisms of DKD are multifactorial, yet haemodynamic and metabolic changes in the early stages of the disease appear to predispose towards irreversible functional loss and histopathological changes. Recent studies highlight the importance of endoplasmic reticulum–mitochondria-associated membranes (ER-MAMs), structures conveying important cellular homeostatic and metabolic effects, in the pathology of DKD. Disruption of ER-MAM integrity in diabetic kidneys is associated with DKD progression, but the regulation of ER-MAMs and their pathogenic contribution remain largely unknown. Exploring the cell-specific components and dynamic changes of ER-MAMs in diabetic kidneys may lead to the identification of new approaches to detect and stratify diabetic patients with DKD. In addition, these insights may lead to novel therapeutic approaches to target and/or reverse disease progression. In this review, we discuss the association of ER-MAMs with key pathomechanisms driving DKD such as insulin resistance, dyslipidaemia, ER stress, and inflammasome activation and the importance of further exploration of ER-MAMs as diagnostic and therapeutic targets in DKD.
Fluorescent imaging probes for <b>in vivo</b> ovarian cancer targeted detection and surgery
Authors: Roberta Solidoro, Antonella Centonze, Morena Miciaccia, Olga Maria Baldelli, Domenico Armenise, Savina Ferorelli, Maria Grazia Perrone, Antonio Scilimati
Journal: Medicinal Research Reviews (2024)

Ovarian cancer is the most lethal gynecological cancer, with a survival rate of approximately 40% at five years from the diagno. The first-line treatment consists of cytoreductive surgery combined with chemotherapy (platinum- and taxane-based drugs). To date, the main prognostic factor is related to the complete surgical resection of tumor lesions, including occult micrometastases. The presence of minimal residual diseases not detected by visual inspection and palpation during surgery significantly increases the risk of disease relapse. Intraoperative fluorescence imaging systems have the potential to improve surgical outcomes. Fluorescent tracers administered to the patient may support surgeons for better real-time visualization of tumor lesions during cytoreductive procedures. In the last decade, consistent with the discovery of an increasing number of ovarian cancer-specific targets, a wide range of fluorescent agents were identified to be employed for intraoperatively detecting ovarian cancer. Here, we present a collection of fluorescent probes designed and developed for fluorescence-guided ovarian cancer surgery. Original articles published between 2011 and November 2022 focusing on fluorescent probes, currently under preclinical and clinical investigation, were searched in PubMed. The keywords used were targeted detection, ovarian cancer, fluorescent probe, near-infrared fluorescence, fluorescence-guided surgery, and intraoperative imaging. All identified papers were English-language full-text papers, and probes were classified based on the location of the biological target: intracellular, membrane, and extracellular.
Bacteriophage Therapy and Current Delivery Strategies for Orthopedic Infections: A SCOPING Review
Authors: Jason Young, Sang W Lee, Mohammad J Shariyate, Alexandria Cronin, John J Wixted, Ara Nazarian, Christopher F Rowley, Edward K Rodriguez
Journal: Journal of Infection (2024)

Interest in phages as adjunctive therapy to treat difficult infections has grown in the last decade. However, phage dosing and delivery for orthopedic infections have not been systematically summarized.
Automatic speech-based assessment to discriminate Parkinson’s disease from essential tremor with a cross-language approach
Authors: Cristian David Rios-Urrego, Jan Rusz, Juan Rafael Orozco-Arroyave
Journal: npj Digital Medicine (2024)

Abstract Parkinson’s disease (PD) and essential tremor (ET) are prevalent movement disorders that mainly affect elderly people, presenting diagnostic challenges due to shared clinical features. While both disorders exhibit distinct speech patterns—hypokinetic dysarthria in PD and hyperkinetic dysarthria in ET—the efficacy of speech assessment for differentiation remains unexplored. Developing technology for automatic discrimination could enable early diagnosis and continuous monitoring. However, the lack of data for investigating speech behavior in these patients has inhibited the development of a framework for diagnostic support. In addition, phonetic variability across languages poses practical challenges in establishing a universal speech assessment system. Therefore, it is necessary to develop models robust to the phonetic variability present in different languages worldwide. We propose a method based on Gaussian mixture models to assess domain adaptation from models trained in German and Spanish to classify PD and ET patients in Czech. We modeled three different speech dimensions: articulation, phonation, and prosody and evaluated the models’ performance in both bi-class and tri-class classification scenarios (with the addition of healthy controls). Our results show that a fusion of the three speech dimensions achieved optimal results in binary classification, with accuracies up to 81.4 and 86.2% for monologue and /pa-ta-ka/ tasks, respectively. In tri-class scenarios, incorporating healthy speech signals resulted in accuracies of 63.3 and 71.6% for monologue and /pa-ta-ka/ tasks, respectively. Our findings suggest that automated speech analysis, combined with machine learning is robust, accurate, and can be adapted to different languages to distinguish between PD and ET patients.
Childhood Obesity Prevention — Focusing on Population-Level Interventions and Equity
Authors: Steven L Gortmaker, Sara N Bleich, David R Williams
Journal: New England Journal of Medicine (2024)

Audio Interview Interview with Ilya Golovaty on platforms offering direct-to-consumer prescribing of medications for weight management. 15m 30s Download AbstractAlthough new weight-loss drugs are important, scholars and policymakers shouldn't lose sight of population-level strategies that can prevent excess weight gain and obesity among children in the first place.
Regular snoring is associated with uncontrolled hypertension
Authors: Bastien Lechat, Ganesh Naik, Sarah Appleton, Jack Manners, Hannah Scott, Duc Phuc Nguyen, Pierre Escourrou, Robert Adams, Peter Catcheside, Danny J. Eckert
Journal: npj Digital Medicine (2024)

Abstract Snoring may be a risk factor for cardiovascular disease independent of other co-morbidities. However, most prior studies have relied on subjective, self-report, snoring evaluation. This study assessed snoring prevalence objectively over multiple months using in-home monitoring technology, and its association with hypertension prevalence. In this study, 12,287 participants were monitored nightly for approximately six months using under-the-mattress sensor technology to estimate the average percentage of sleep time spent snoring per night and the estimated apnea-hypopnea index (eAHI). Blood pressure cuff measurements from multiple daytime assessments were averaged to define uncontrolled hypertension based on mean systolic blood pressure≥140 mmHg and/or a mean diastolic blood pressure ≥90 mmHg. Associations between snoring and uncontrolled hypertension were examined using logistic regressions controlled for age, body mass index, sex, and eAHI. Participants were middle-aged (mean ± SD; 50 ± 12 y) and most were male (88%). There were 2467 cases (20%) with uncontrolled hypertension. Approximately 29, 14 and 7% of the study population snored for an average of &gt;10, 20, and 30% per night, respectively. A higher proportion of time spent snoring (75th vs. 5th; 12% vs. 0.04%) was associated with a ~1.9-fold increase (OR [95%CI]; 1.87 [1.63, 2.15]) in uncontrolled hypertension independent of sleep apnea. Multi-night objective snoring assessments and repeat daytime blood pressure recordings in a large global consumer sample, indicate that snoring is common and positively associated with hypertension. These findings highlight the potential clinical utility of simple, objective, and noninvasive methods to detect snoring and its potential adverse health consequences.
Clinical impact of genetic alterations including germline DDX41 mutations in MDS/low-blast count AML patients treated with azacitidine-based regimens
Authors: Marie Sébert, Lucie Freiman, Cendrine Chaffaut, Agnès Guerci, Pierre Peterlin, Sylvain Thépot, Odile Beyne-Rauzy, Sophie Park, Thomas Cluzeau, Fatiha Chermat, Pierre Fenaux, Claude Preudhomme, Emmanuelle Clappier, Sylvie Chevret, Lionel Adès, Nicolas Duployez, Matthieu Duchmann
Journal: Leukemia (2024)
The effects of <i>de novo</i> mutation on gene expression and the consequences for fitness in <i>Chlamydomonas reinhardtii</i>
Authors: Eniolaye J Balogun, Rob W Ness
Journal: Molecular Biology and Evolution (2024)

Abstract Mutation is the ultimate source of genetic variation, the bedrock of evolution. Yet, predicting the consequences of new mutations remains a challenge in biology. Gene expression provides a potential link between a genotype and its phenotype. But the variation in gene expression created by de novo mutation and the fitness consequences of mutational changes to expression remain relatively unexplored. Here, we investigate the effects of &amp;gt;2,600 de novo mutations on gene expression across the transcriptome of 28 mutation accumulation lines derived from 2 independent wild-type genotypes of the green algae Chlamydomonas reinhardtii. We observed that the amount of genetic variance in gene expression created by mutation (Vm) was similar to the variance that mutation generates in typical polygenic phenotypic traits and approximately 15-fold the variance seen in the limited species where Vm in gene expression has been estimated. Despite the clear effect of mutation on expression, we did not observe a simple additive effect of mutation on expression change, with no linear correlation between the total expression change and mutation count of individual MA lines. We therefore inferred the distribution of expression effects of new mutations to connect the number of mutations to the number of differentially expressed genes (DEGs). Our inferred DEE is highly L-shaped with 95% of mutations causing 0-1 DEG while the remaining 5% are spread over a long tail of large effect mutations that cause multiple genes to change expression. The distribution is consistent with many cis-acting mutation targets that affect the expression of only 1 gene and a large target of trans-acting targets that have the potential to affect tens or hundreds of genes. Further evidence for cis-acting mutations can be seen in the overabundance of mutations in or near differentially expressed genes. Supporting evidence for trans-acting mutations comes from a 15:1 ratio of DEGs to mutations and the clusters of DEGs in the co-expression network, indicative of shared regulatory architecture. Lastly, we show that there is a negative correlation with the extent of expression divergence from the ancestor and fitness, providing direct evidence of the deleterious effects of perturbing gene expression.
The impact of indoor pollution on asthma‐related outcomes: A systematic review for the EAACI guidelines on environmental science for allergic diseases and asthma
Authors: Ioana Agache, Carlos Canelo‐Aybar, Isabella Annesi‐Maesano, Lorenzo Cecchi, Benedetta Biagioni, Fan Chung, Gennaro D'Amato, Athanasios Damialis, Stefano Del Giacco, Leticia De las Vecillas, Javier Dominguez‐Ortega, Carmen Galàn, Stefanie Gilles, Mattia Giovannini, Stephen Holgate, Mohamed Jeebhay, Kari Nadeau, Nikolaos Papadopoulos, Santiago Quirce, Joaquin Sastre, Claudia Traidl‐Hoffmann, Jolanta Walusiak‐Skorupa, Bernardo Sousa‐Pinto, Josefina Salazar, L. Yesenia Rodríguez‐Tanta, Yahveth Cantero, Camila Montesinos‐Guevara, Yang Song, Giancarlo Alvarado‐Gamarra, Ivan Sola, Pablo Alonso‐Coello, Wendy Nieto‐Gutierrez, Marek Jutel, Cezmi A. Akdis
Journal: Allergy (2024)

Abstract Systematic review using GRADE of the impact of exposure to volatile organic compounds (VOCs), cleaning agents, mould/damp, pesticides on the risk of (i) new‐onset asthma (incidence) and (ii) adverse asthma‐related outcomes (impact). MEDLINE, EMBASE and Web of Science were searched for indoor pollutant exposure studies reporting on new‐onset asthma and critical and important asthma‐related outcomes. Ninety four studies were included: 11 for VOCs (7 for incidenceand 4 for impact), 25 for cleaning agents (7 for incidenceand 8 for impact), 48 for damp/mould (26 for incidence and 22 for impact) and 10 for pesticides (8 for incidence and 2 for impact). Exposure to damp/mould increases the risk of new‐onset wheeze (moderate certainty evidence). Exposure to cleaning agents may be associated with a higher risk of new‐onset asthma and with asthma severity (low level of certainty). Exposure to pesticides and VOCs may increase the risk of new‐onset asthma (very low certainty evidence). The impact on asthma‐related outcomes of all major indoor pollutants is uncertain. As the level of certainty is low or very low for most of the available evidence on the impact of indoor pollutants on asthma‐related outcomes more rigorous research in the field is warranted.
Intravenous gentamicin therapy induces functional type VII collagen in patients with recessive dystrophic epidermolysis bullosa: an open-label clinical trial
Authors: David T Woodley, Michelle Hao, Andrew Kwong, Brandon Levian, Jon Cogan, Yingping Hou, Daniel Mosallaei, Elana Kleinman, Kate Zheng, Claire Chung, Gene Kim, David Peng, Mei Chen
Journal: British Journal of Dermatology (2024)

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable widespread blistering skin disorder caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils.
A Critical Appraisal of DNA Transfer from Plants to Parasitic Cyst Nematodes
Authors: Itsuhiro Ko, Olaf Prosper Kranse, Beatrice Senatori, Sebastian Eves-van den Akker
Journal: Molecular Biology and Evolution (2024)

Abstract Plant-parasitic nematodes are one of the most economically important pests of crops. It is widely accepted that horizontal gene transfer—the natural acquisition of foreign genes in parasitic nematodes—contributes to parasitism. However, an apparent paradox has emerged from horizontal gene transfer analyses: On the one hand, distantly related organisms with very dissimilar genetic structures (i.e. bacteria), and only transient interactions with nematodes as far as we know, dominate the list of putative donors, while on the other hand, considerably more closely related organisms (i.e. the host plant), with similar genetic structure (i.e. introns) and documented long-term associations with nematodes, are rare among the list of putative donors. Given that these nematodes ingest cytoplasm from a living plant cell for several weeks, there seems to be a conspicuous absence of plant-derived cases. Here, we used comparative genomic approaches to evaluate possible plant-derived horizontal gene transfer events in plant parasitic nematodes. Our evidence supports a cautionary message for plant-derived horizontal gene transfer cases in the sugar beet cyst nematode, Heterodera schachtii. We propose a 4-step model for horizontal gene transfer from plant to parasite in order to evaluate why the absence of plant-derived horizontal gene transfer cases is observed. We find that the plant genome is mobilized by the nematode during infection, but that uptake of the said “mobilome” is the first major barrier to horizontal gene transfer from host to nematode. These results provide new insight into our understanding of the prevalence/role of nucleic acid exchange in the arms race between plants and plant parasites.
Self‐Organization of Long‐Lasting Human Endothelial Capillary‐Like Networks Guided by DLP Bioprinting
Authors: Elsa Mazari‐Arrighi, Matthieu Lépine, Dmitry Ayollo, Lionel Faivre, Jérôme Larghero, François Chatelain, Alexandra Fuchs
Journal: Advanced Healthcare Materials (2024)

Tissue engineering holds great promise for regenerative medicine, drug discovery, and as an alternative to animal models. However, as soon as the dimensions of engineered tissue exceed the diffusion limit of oxygen and nutriments, a necrotic core forms leading to irreversible damage. To overcome this constraint, the establishment of a functional perfusion network is essential. In this work, digital light processing bioprinting is used to encapsulate endothelial progenitor cells (EPCs) in 3D light-cured hydrogel scaffolds to guide them toward vascular network formation. In these scaffolds, EPCs proliferate and self-organize within a few days into branched tubular structures with predefined geometry, forming capillary-like vascular tubes or trees of diameters in the range of 10 to 100 µm. Presenting a confluent monolayer wall of cells strongly connect by tight junctions around a central lumen-like space, these structures can be microinjected with a fluorescent dye and are stable for several weeks in vitro. These endothelial structures can be recovered and manipulated in an alginate patch without altering their shape or viability. This approach opens new opportunities for future applications, such as stacking with other cell sheets or multicellular constructs to yield bioengineered tissue with higher complexity and functionality.
Genomic risk scores in prostate cancer: polygenic yes, but are they poly-ancestral?
Authors: Arnab Basu, Soroush Rais-Bahrami
Journal: JNCI Journal of the National Cancer Institute (2024)

There is substantial heterogeneity in the biology and clinical course of prostate cancer across patients with this diagnosis.Although prostate cancer is the most common cancer and second-leading cause of cancer-related mortality in American men, unlike lung, breast, or colon cancer, there are no consistent guidelines that support universal screening because of the risk of false positives and the potential for overtreatment.Thus, there is great interest in evaluating reliable biomarkers of elevated prostate cancer risk.Polygenic risk scores (PRSs) are a potential tools to improve clinical outcomes by identifying patients who may benefit from more intensive monitoring or therapy.Ancestry plays an important role in prostate cancer biology, with African American patients having a 64% greater risk of developing prostate cancer than their European counterparts (1).Further, African American patients experience worse outcomes, with an earlier age of presentation and higher rates of metastatic disease (2).Unfortunately, many risk stratification tools have been developed on European ancestry cohorts that may not be optimal for evaluating prostate cancer risk in other ancestral groups (3).In this issue of the Journal, Lee and colleagues (4) examine a polygenic hazard score (PHS)-specifically, PHS290-in a large cohort of 36 717 veterans, among whom 10 297 (28.04%) are of African American ancestry.Their investigation focuses retrospectively on patients undergoing their first prostate biopsy, and they correlate the germline risk of prostate cancer based on the polygenic hazard score with subsequent positive biopsy findings.The results suggest that although the PHS290 is associated with a higher risk of positive biopsy results, it performs better in patients of European ancestry (odds ratio [OR] ¼ 3.89, 95% confidence interval [CI] ¼ 3.62 to 4.18) than in those of African ancestry (OR ¼ 2.18, 95% CI ¼ 1.93 to 2.47).PHS290 also appears to be associated with an elevated risk of diagnosing more aggressive prostate cancer, although it is not specific for it.These findings are congruent with other studies.In a study by Kim et al. ( 5), 3 distinct polygenic risk scores were validated in a sub-Saharan cohort.These tools included the PRS269, which is a unique score that uses ancestry-specific weights; another 147marker polygenic risk score developed on a European population;
Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide
Authors: Hong Sheng Cheng, Yuk Kien Chong, Eldeen Kai Yi Lim, Xin Yi Lee, Qing You Pang, Wisna Novera, Charlie Marvalim, Jeannie Xue Ting Lee, Beng Ti Ang, Carol Tang, Nguan Soon Tan
Journal: Neuro-Oncology (2024)

Abstract Background Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype. Methods We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells and public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays, and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis. Results Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favorably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintain temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts. Conclusions Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.