tbuckley/cabot-search huggingface dataset:
Quality assessment of LNP-RNA therapeutics with orthogonal analytical techniques
Authors: Jeremie Parot, Dora Mehn, Hanna Jankevics, Natalia Markova, Michele Carboni, Camilla Olaisen, Andrea D. Hoel, Margrét S. Sigfúsdóttir, Florian Meier, Roland Drexel, Gabriele Vella, Birgitte McDonagh, Terkel Hansen, Huong Bui, Geir Klinkenberg, Torkild Visnes, Sabrina Gioria, Patricia Urban-Lopez, Adriele Prina-Mello, Sven Even Borgos, Fanny Caputo, Luigi Calzolai
Journal: Journal of Controlled Release (2024)

The availability of analytical methods for the characterization of lipid nanoparticles (LNPs) for in-vivo intracellular delivery of nucleic acids is critical for the fast development of innovative RNA therapies. In this study, analytical protocols to measure (i) chemical composition, (ii) drug loading, (iii) particle size, concentration, and stability as well as (iv) structure and morphology were evaluated and compared based on a comprehensive characterization strategy linking key physical and chemical properties to in-vitro efficacy and toxicity. Furthermore, the measurement protocols were assessed either by testing the reproducibility and robustness of the same technique in different laboratories, or by a correlative approach, comparing measurement results of the same attribute with orthogonal techniques. The characterization strategy and the analytical measurements described here will have an important role during formulation development and in determining robust quality attributes ultimately supporting the quality assessment of these innovative RNA therapeutics.
Screening for Speech and Language Delay and Disorders in Children
Authors: Michael J. Barry, Wanda K. Nicholson, Michael Silverstein, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, Carlos Roberto Jaén, Li Li, Carol M. Mangione, Gbenga Ogedegbe, Goutham Rao, John M. Ruiz, James Stevermer, Joel Tsevat, Sandra Millon Underwood, John B. Wong
Journal: JAMA (2024)

Speech and language delays and disorders can pose significant problems for children and their families. Evidence suggests that school-aged children with speech or language delays may be at increased risk of learning and literacy disabilities, including difficulties with reading and writing. The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate benefits and harms of screening for speech and language delay and disorders in children 5 years or younger. Asymptomatic children 5 years or younger whose parents or clinicians do not have specific concerns about their speech, language, hearing, or development. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for speech and language delay and disorders in children who do not present with signs or symptoms or parent/caregiver concerns. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for speech and language delay and disorders in children 5 years or younger without signs or symptoms. (I statement).
Laryngectomy
Authors: Anne Pitkin
Journal: JAMA (2024)

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Development of an environmentally sensitive fluorescent peptide probe for MrgX2 and application in ligand screening of peptide antibiotics
Authors: Yajing Hou, Jiayu Lu, Mengyao Yi, Xia Cui, Lu Cao, Xianpeng Shi, Pengchong Wang, Nan Zhou, Peng Zhang, Cheng Wang, Huaizhen He, Delu Che
Journal: Journal of Controlled Release (2024)
Concurrent Heat and Air Pollution Exposures among People Experiencing Homelessness
Authors: Zachary Van Tol, Jennifer K. Vanos, Ariane Middel, Kristin M. Ferguson
Journal: Environmental Health Perspectives (2024)

Extreme heat and air pollution are important human health concerns; exposure can affect mental and physical well-being, particularly during periods of co-occurrence. Yet, the impacts on people are largely determined by underlying health conditions, coupled with the length and intensity of exposure. Preexisting adverse health conditions and prolonged exposure times are more common for people experiencing homelessness, particularly those with intersectional identity characteristics (e.g., disease, ability, age, etc.). Partially due to methodological limitations, such as data scarcity, there is a lack of research at the intersection of this at-risk population within the climate-health domain.
Robot-assisted radical cystectomy with intracorporeal urinary diversion: an updated systematic review and meta-analysis of its differential effect on effectiveness and safety
Authors: Shi Fu, HongJin Shi, Zhinan Fan, Jinze Li, Ting Luan, Haonan Dong, Jincheng Wang, Shuwen Chen, Jinsong Zhang, Jiansong Wang, Mingxia Ding, Haifeng Wang
Journal: International Journal of Surgery (2024)

Background: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being used in recent years. Whether iRARC offers advantages over open radical cystectomy (ORC) remains controversial. This study aimed to compare the difference of perioperative outcomes, oncological outcomes and complications between iRARC and ORC. Methods: The PubMed, Embase, Cochrane Library, Web of Science and CNKI databases were searched in July 2023 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were identified to be eligible if they compared perioperative outcomes, oncological outcomes and complications in patients who underwent iRARC with ORC. Results: Twenty-two studies involving 7020 patients were included. Compared to ORC, iRARC was superior for estimated blood loss [estimated blood loss (EBL) weighted mean difference (WMD): −555.52; 95% CI, −681.64 to −429.39; P &lt;0.001], blood transfusion rate [odds ratio (OR): 0.16; 95% CI, 0.09–0.28; P &lt;0.001], length of hospital stay [length of hospital stay (LOS) WMD: −2.05; 95% CI, −2.93 to −1.17; P &lt;0.001], Clavien–Dindo grades ≥III complication rate [30 days: OR: 0.57; 95% CI 0.44–0.75; P &lt;0.001; 90 days: OR: 0.71; 95% CI 0.60–0.84; P &lt;0.001], and positive surgical margin [positive surgical margin (PSM) OR: 0.65; 95% CI 0.49–0.85; P =0.002]. However, iRARC had a longer operative time [operative time (OT) WMD: 68.54; 95% CI 47.41–89.67; P &lt;0.001] and a higher rate of ureteroenteric stricture [ureteroenteric stricture (UES) OR: 1.56; 95% CI 1.16–2.11; P =0.003]. Time to flatus, time to bowel, time to regular diet, readmission rate, Clavien–Dindo grades less than III complication rate for iRARC were similar to that for ORC. Interestingly, the results of subgroup analysis revealed no difference in EBL between iRARC and ORC when the diversion type was neobladder. When the ileal conduit was selected as the diversion type, the LOS was similar in both procedures. Conclusion: Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion appears to be superior to open radical cystectomy in terms of effectiveness and safety. However, attention should be paid to the occurrence of ureteroenteric stricture during follow-up.
<i>LT</i> and <i>SOX9</i> expression are associated with gene sets that distinguish Merkel cell polyomavirus (MCPyV)-positive and MCPyV-negative Merkel cell carcinoma
Authors: Juan Torre-Castro, Marta Rodríguez, Ruth Alonso-Alonso, María Dolores Mendoza Cembranos, Jesús Frutos Díaz-Alejo, Marcos Rebollo-González, Jennifer Borregón, Laura Nájera Botello, Ignacio Mahillo-Fernández, Mathab Samimi, Thibault Kervarrec, Luis Requena, Miguel Ángel Piris
Journal: British Journal of Dermatology (2024)

Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways.
Artificial pancreases for type 1 diabetes: Better access is “watershed moment”—but delivery is key
Authors: Gareth Iacobucci
Journal: BMJ (2024)

Hybrid closed loop systems are being hailed as the greatest advance in type 1 diabetes care since the discovery of insulin. The UK is leading the way with new NICE guidance, but there is work to do to avoid a postcode lottery, writes <b>Gareth Iacobucci</b>
Alcohol Use Disorder Treatment: Problems and Solutions
Authors: George F. Koob
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Alcohol use disorder (AUD) afflicts over 29 million individuals and causes more than 140,000 deaths annually in the United States. A heuristic framework for AUD includes a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that provides a starting point for exploring the heterogeneity of AUD with regard to treatment. Effective behavioral health treatments and US Food and Drug Administration–approved medications are available but greatly underutilized, creating a major treatment gap. This review outlines challenges that face the alcohol field in closing this treatment gap and offers solutions, including broadening end points for the approval of medications for the treatment of AUD; increasing the uptake of screening, brief intervention, and referral to treatment; addressing stigma; implementing a heuristic definition of recovery; engaging early treatment; and educating health-care professionals and the public about challenges that are associated with alcohol misuse. Additionally, this review focuses on broadening potential targets for the development of medications for AUD by utilizing the three-stage heuristic model of addiction that outlines domains of dysfunction in AUD and the mediating neurobiology of AUD.
A mucus production programme promotes classical pancreatic ductal adenocarcinoma
Authors: Claudia Tonelli, Georgi N Yordanov, Yuan Hao, Astrid Deschênes, Juliene Hinds, Pascal Belleau, Olaf Klingbeil, Erin Brosnan, Abhishek Doshi, Youngkyu Park, Ralph H Hruban, Christopher R Vakoc, Alexander Dobin, Jonathan Preall, David A Tuveson
Journal: Gut (2024)

Objective The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. Design We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. Results Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA — the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo . The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2 /IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation. Conclusions Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.
Blood eosinophils and fractional exhaled nitric oxide are prognostic and predictive biomarkers in childhood asthma
Authors: Leonard B Bacharier, Ian D Pavord, Jorge F Maspero, Daniel J Jackson, Alessandro G Fiocchi, Xuezhou Mao, Juby A Jacob-Nara, Yamo Deniz, Elizabeth Laws, Leda P Mannent, Nikhil Amin, Bolanle Akinlade, Heribert W Staudinger, David J Lederer, Megan Hardin
Journal: Journal of Allergy and Clinical Immunology (2024)
Baseline Serum neutrophil-to-lymphocyte ratio in acral melanoma compared with nonacral melanoma and its prognostic significance
Authors: Myoung Eun Choi, Joon Min Jung, Do Hyung Kim, Chong Hyun Won, Sung Eun Chang, Mi Woo Lee, Woo Jin Lee
Journal: Journal of the American Academy of Dermatology (2024)
Influence of pathogenic filaggrin variants on dupilumab treatment in atopic dermatitis
Authors: Julia Clabbers, Celeste Boesjes, Lotte Spekhorst, Marike W. van Gisbergen, Emmy Maas, Josephine Marshall, Renske Janssen, Miranda Janssen, Nicolaas Zuithoff, Peter Steijlen, Marlies de Graaf, Michel van Geel, Marjolein de Bruin-Weller, Antoni Gostyński
Journal: Journal of Allergy and Clinical Immunology (2024)

Background: Pathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD).Objective: To evaluate the influence of FLG variants on the effectiveness of dupilumab treatment in AD. Methods:This prospective observational study included adult AD patients treated with dupilumab from the BioDay Registry.FLG was analysed with smMIP targeted sequencing.Novel mutations were confirmed by Sanger sequencing.Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI) and Patient Oriented Eczema Measure (POEM) were assessed at baseline, week 16 and 52.Results: Genetic analysis of 285 included patients showed bi-allelic pathogenic variants (FLG-/-) in n=41 (14%), mono-allelic pathogenic variants (FLG-/+) in n=64 (23%) and wild-type alleles (FLG+/+) in n=180 (63%).Three novel pathogenic variants were found.We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI and total POEM scores for patients with and without pathogenic FLG variants at all time points.The FLG-/-group showed significantly higher POEM flaking and dryness scores at week 16 (p<0.001and p=0.002, respectively) and 52 (p<0.001 and p=0.016, respectively) compared to FLG+/+, and also significant differences compared with FLG-/+, while differences in delta scores were nonsignificant. Conclusion:This study suggests that the effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants.However, patients with bi-allelic pathogenic FLG variants tended to have a drier skin before and during dupilumab treatment compared to patients with mono-allelic pathogenic variants or wild-type alleles.
A septal-ventral tegmental area circuit drives exploratory behavior
Authors: Petra Mocellin, Oliver Barnstedt, Kevin Luxem, Hiroshi Kaneko, Silvia Vieweg, Julia U. Henschke, Dennis Dalügge, Falko Fuhrmann, Anna Karpova, Janelle M.P. Pakan, Michael R. Kreutz, Sanja Mikulovic, Stefan Remy
Journal: Neuron (2024)

To survive, animals need to balance their exploratory drive with their need for safety. Subcortical circuits play an important role in initiating and modulating movement based on external demands and the internal state of the animal; however, how motivation and onset of locomotion are regulated remain largely unresolved. Here, we show that a glutamatergic pathway from the medial septum and diagonal band of Broca (MSDB) to the ventral tegmental area (VTA) controls exploratory locomotor behavior in mice. Using a self-supervised machine learning approach, we found an overrepresentation of exploratory actions, such as sniffing, whisking, and rearing, when this projection is optogenetically activated. Mechanistically, this role relies on glutamatergic MSDB projections that monosynaptically target a subset of both glutamatergic and dopaminergic VTA neurons. Taken together, we identified a glutamatergic basal forebrain to midbrain circuit that initiates locomotor activity and contributes to the expression of exploration-associated behavior.
Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy
Authors: Huijie Feng, Jerome Clatot, Keisuke Kaneko, Marco Flores-Mendez, Eric R. Wengert, Carly Koutcher, Emily Hoddeson, Emily Lopez, Demetrius Lee, Leroy Arias, Qiansheng Liang, Xiaohong Zhang, Ala Somarowthu, Manuel Covarrubias, Martin J. Gunthorpe, Charles H. Large, Naiara Akizu, Ethan M. Goldberg
Journal: Cell Reports Medicine (2024)

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.
Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment
Authors: Wei Wei, Yali Liu, Yuanlong Hou, Shuqi Cao, Zhuo Chen, Youying Zhang, Xiaoying Cai, Qingyuan Yan, Ziguang Li, Yonggui Yuan, Guangji Wang, Xiao Zheng, Haiping Hao
Journal: Cell Metabolism (2024)
Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle
Authors: Giovanna Sonsalla, Ana Belen Malpartida, Therese Riedemann, Mirjana Gusic, Ejona Rusha, Giorgia Bulli, Sonia Najas, Aleks Janjic, Bob A. Hersbach, Pawel Smialowski, Micha Drukker, Wolfgang Enard, Jochen H.M. Prehn, Holger Prokisch, Magdalena Götz, Giacomo Masserdotti
Journal: Neuron (2024)

Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.
Reply to Carmen Gravina, Matteo Romagnoli, Antonio Nacchia, et al.’s Letter to the Editor re: Edward Lambert, Emmanuel Chartier-Kastler, Christophe Vaessen, et al. Robot-assisted Periprostatic Artificial Urinary Sphincter Implantation in Men with Neurogenic Stress Urinary Incontinence: Description of the Surgical Technique and Comparison of Long-term Functional Outcomes with the Open Approach. Eur Urol. 2024;85:139–145
Authors: Edward Lambert, Emmanuel Chartier-Kastler, Christophe Vaessen, Aurélien Beaugerie, Juliette Cotte, Morgan Rouprêt, Pierre Mozer, Jérôme Parra, Thomas Seisen, Louis Lenfant
Journal: European Urology (2024)
NKG2A<sup>+</sup>CD8<sup>+</sup>T cells infiltration determines immunosuppressive contexture and inferior response to immunotherapy in clear cell renal cell carcinoma
Authors: Youqi Qiu, Li Liu, Wenbin Jiang, Ziyang Xu, Jiahao Wang, Siyuan Dai, Jianming Guo, Jiejie Xu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immunotherapy is gaining momentum, but current treatments have limitations in terms of beneficiaries. Clear cell renal cell carcinoma (ccRCC) harbors the highest expression of human leukocyte antigen E (HLA-E), ligand of NKG2A, among all solid tumors. In this study, we aim to investigate the role of NKG2A+CD8+ T cells in tumor microenvironment and its potential as a novel target in ccRCC. This study included four independent cohorts, including 234 patients from Zhongshan cohort (ZSHC) who underwent partial or radical nephrectomy at Zhongshan Hospital, and 117 metastatic patients from metastatic Zhongshan cohort (ZSHC-metastatic renal cell carcinoma) who were treated with immune checkpoint inhibitor or tyrosine kinase inhibitor alone. We also incorporated a cohort of 530 patients diagnosed with ccRCC from The Cancer Genome Atlas (referred to as TCGA-kidney renal clear cell carcinoma) and 311 patients from CheckMate cohort for bioinformatics exploration and hypothesis validation. Fresh surgical specimens from 15 patients who underwent ccRCC surgery at Zhongshan Hospital were collected for flow cytometry analysis. Another 10 fresh surgical specimens were used to investigate the therapeutic potential of NKG2A blockade after in vitro intervention. The infiltration of NKG2A+CD8+ T cells was assessed using immunohistochemical staining, flow cytometry, and immunofluorescence staining in ZSHC cohort. Patients with higher infiltration of NKG2A+CD8+ T cells in ccRCC exhibited shorter overall survival and resistance to immunotherapy. NKG2A+CD8+ T cells expressed upregulated checkpoint molecules and displayed impaired effector functions, along with tissue-residency characteristics. Combination of programmed cell death protein-1 (PD-1) blockade and NKG2A blockade demonstrated an enhanced capability in reactivating CD8+ T cells effector functions. Intense infiltration of NKG2A+CD8+ T cells were associated with poorer prognosis and response to immunotherapy. NKG2A blockade combined with current immunotherapy exhibited a robust ability to reactivate CD8+ T cells effector functions.