tbuckley/cabot-search huggingface dataset:
Tuberculosis Preventive Treatment in High TB-Burden Settings: A State-of-the-Art Review
Authors: Violet Chihota, Makaita Gombe, Amita Gupta, Nicole Salazar-Austin, Tess Ryckman, Christopher J. Hoffmann, Sylvia LaCourse, Jyoti S. Mathad, Vidya Mave, Kelly E. Dooley, Richard E. Chaisson, Gavin Churchyard
Journal: Drugs (2024)

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The burden is highest in some low- and middle-income countries. One-quarter of the world's population is estimated to have been infected with TB, which is the seedbed for progressing from TB infection to the deadly and contagious disease itself. Although some individuals may clear their infections through innate and acquired immunity, many do not. People living with HIV, TB-exposed household contacts, other individuals recently infected, and immunosuppressed individuals are at especially high risk of progressing to TB disease. There have been major advances in recent years to support the programmatic management of TB infection. New tests of infection, including those that predict progression to TB disease, have become available. Numerous World Health Organization-recommended TB preventive treatment (TPT) regimens are available for all ages and for both drug-susceptible and drug-resistant TB infection. All regimens are generally safe, efficacious, and cost effective and have a low risk of generating resistance. TPT is recommended for pregnant women who are at risk for developing TB, but some regimens are associated with an increased likelihood of poor obstetric and fetal outcomes, and newer regimens have not yet been tested in pregnancy. New formulations of rifapentine-based TPT have been developed, and the cost has been radically reduced. Innovative models of delivery to support the scale up of TPT have been developed. Modeling suggests that scaling up TPT, especially regimens with optimal target product profile characteristics, can contribute substantially to ending the TB epidemic. The global uptake of TPT has increased substantially, especially for people living with HIV. Implementation gaps remain, particularly for children, pregnant women, and other household contacts. Further innovation is required to support the continued scale up of TPT and to contribute to ending the TB epidemic.
Nanopore Sequencing as a Cutting-Edge Technology for Medulloblastoma Classification
Authors: Mathilde Filser, Jacob Torrejon, Kevin Merchadou, Christelle Dufour, Elodie Girard, Christine Bourneix, Elisa Lemaître, Tarek Gharsalli, Riwan Brillet, Jennifer Wong, David Gentien, Audrey Rapinat, Nicolas Servant, Alexandre Vasiljevic, Anne Isabelle Bertozzi, Sandra Raimbault, Arnault Tauziede Espariat, Benoit Lhermitte, Cécile Faure-Conter, Céline Icher, Claire Berger, Claude Alain Maurage, Damien Bodet, David Meyronet, Emmanuelle Uro-Coste, Emilie De Carli, Fabien Forest, Gilles Palenzuela, Guillaume Chotard, Guillaume Gauchotte, Helene Sudour, Ludovic Mansuy, Marianna Deparis, Matthias Tallegas, Maxime Faisant, Natacha Entz-Werle, Pascale Varlet, Pierre Leblond, Sophie Michalak-Provost, Stéphanie Proust Houdemont, Valérie Rigau, François Doz, Olivier Delattre, Franck Bourdeaut, Olivier Ayrault, Julien Masliah-Planchon
Journal: Neuro-Oncology (2024)

Abstract Background Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into four molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient’s management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities. Methods We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB. Results Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4% respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB. Conclusion This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification.
Autophagy Modulates Glioblastoma Cell Sensitivity to Selinexor-mediated XPO1 inhibition
Authors: Yongjian Tang, Lisa Sprinzen, Yukinori Terada, Karrie M Kiang, Chuntao Li, Yu Zeng, Fangkun Liu, Hongshu Zhou, Xisong Liang, Jianzhong Zhang, Russell O Pieper, Bo Chen, Liyang Zhang
Journal: Neuro-Oncology (2024)

Abstract Background Selinexor is a selective inhibitor of exportin-1 (XPO1), a key mediator of the nucleocytoplasmic transport for molecules critical to tumor cell survival. Selinexor’s lethality is generally associated with the induction of apoptosis, and in some cases, with autophagy-induced apoptosis. We performed this study to determine Selinexor’s action in glioblastoma (GBM) cells, which are notoriously resistant to apoptosis. Methods Patient-derived GBM cells were treated with Selinexor, and drug response and autophagy levels were monitored. Homozygous C528S XPO1 mutant GBM43 cells were generated by CRISPR/Cas9 editing. Single Selinexor or combination treatment with autophagy inhibitors was evaluated. In addition, bulk-tissue, single-cell, and spatial transcriptome were analyzed, and molecular docking was performed. Results Although all cell lines exhibited a dose- and time-dependent reduction of cell viability, the most profound molecular response to Selinexor was induction of autophagy instead of apoptosis. Selinexor-induced autophagy was an on-target consequence of XPO1 inhibition, and could be mitigated by expression of a mutant, Selinexor-resistant form of XPO1, and Selinexor-induced autophagy was related at least in part to nuclear trapping of the transcription factor TFEB. Furthermore, genetic or pharmacologic suppression of autophagy sensitized the cells to Selinexor-induced toxicity in association with the induction of apoptosis. Finally, in intracranial PDX studies, the combination of Selinexor with the autophagy inhibitor chloroquine significantly impeded tumor growth and extended mouse survival relative to single-agent treatment. Conclusion These results suggest that activation of autophagy confers a protective mechanism against Selinexor in GBM cells, and that the combination of Selinexor with autophagy inhibitors may serve as a viable means to enhance Selinexor-induced cell death.
Therapeutic effect of novel drug candidate, PRG-N-01, on NF2 syndrome-related tumor
Authors: Yeon-Ho Chung, Soyoung Park, Moonyoung Lee, Jongwon Lee, Yeongseon Ji, Yi Jin Song, Tae-Gyun Woo, Eunbyeol Shin, Songyoung Baek, Young Jun Hwang, Yuju Kim, Minju Kim, Jin Han, Hong-Rae Kim, Jungmin Choi, Bae-Hoon Kim, Bum-Joon Park
Journal: Neuro-Oncology (2024)

Abstract Background NF2-related schwannomatosis (NF2-SWN) is associated with multiple benign tumors in the nervous system. NF2-SWN, caused by mutations in the NF2 gene, has developed into intracranial and spinal schwannomas. Because of the high surgical risk and frequent recurrence of multiple tumors, targeted therapy is necessary. However, there are no approved drugs. Methods We examined the action mechanism of PRG-N-01, a candidate molecule for NF2-SWN, through the direct binding assay and mass spectrometry. For in vitro anti-proliferative experiments, primary cells derived from NF2 mouse model and patient tumors, were treated with PRG-N-01. The in vivo therapeutic and preventive efficacy was validated via intraperitoneal and oral administration in NF2 mouse model (Postn-Cre; Nf2f/f). Gene expression profile in the DRG of mouse model was explored by RNA sequencing. The pharmacological properties of PRG-N-01 were analyzed through the preclinical study. Results PRG-N-01 binds to the N-terminal extremity of TGFβR1 (TβR1) kinase domain, where TβR1 and RKIP interact, inhibiting the binding and preventing degradation of RKIP. In vivo administration in the mouse model suppressed schwannoma progression in the DRG. Early oral administration of the PRG-N-01 also demonstrated preventive effects on NF2-SWN. PRG-N-01 treatment suppressed tumor growth genes while upregulating genes related to for normal cell metabolism and schwann cell differentiation in DRG. PRG-N-01 showed druggable properties through the preclinical study including ADME, pharmacodynamics, pharmacokinetics and toxicology. Conclusions Together, our study provides the rationale and critical data for a prospective clinical trial of PRG-N-01 in NF2-SWN patients indicating PRG-N-01 as a promising candidate for the treatment.
Self-assembled natural triterpenoids for the delivery of cyclin-dependent kinase 4/6 inhibitors to enhance cancer chemoimmunotherapy
Authors: Yongbo Zhang, Yajie Lian, Conglei Zhou, Jianjun Cheng, Shuang Zhao, Hongjun Liu, Jiacheng Wang, Xin Lu, Jiahua Shi, Guanhua Du
Journal: Journal of Controlled Release (2024)
A Self-Gelling Hemostatic Powder Boosting Radiotherapy-Elicited NK Cell Immunity to Combat Postoperative Hepatocellular Carcinoma Relapse
Authors: Yihang Gong, Yusheng Cheng, Fanxin Zeng, Xiaoquan Liu, Yang Yang, Feng Zhang, Chaoyao Wen, Fan Yang, Hua Li, Yizhan He, Beibei Ni, Yan Xu, Lan Xiao, Qi Zhang, Lei Zhou, Jun Zheng, Wenjie Chen
Journal: Biomaterials (2024)
Iodine-131 radioembolization boosts the immune activation enhanced by icaritin/resiquimod in hepatocellular carcinoma
Authors: Xinyi Li, Yuyi Qian, Xin Lu, Mingzhen Xu, Simin He, Jianping Zhang, Shaoli Song
Journal: Journal of Controlled Release (2024)

Transarterial radioembolization (TARE) is a recommended locoregional strategy for intermediate hepatocellular carcinoma (HCC), whereas, the effect is insufficient to reverse the immunosuppression tumor microenvironment, and the overall benefits for patients remain to be improved. In this study, a multifunctional microsphere (MS)
Polymer-siRNA nanovectors for treating lung inflammation
Authors: Ritabrita Goswami, Harini Nagaraj, Yagiz Anil Cicek, Nourina Nasim, Sarah S Mirza, Muhammad Aamir Hassan, Rukmini Mhaske, Deepthika M Saravanan, Cedar Noonan, Edward Pham, Jesse Mager, Vincent M Rotello
Journal: Journal of Controlled Release (2025)
Nose-to-brain delivery of lithium via a sprayable in situ-forming hydrogel composed of chelating starch nanoparticles
Authors: Andrew Lofts, Fahed Abu-Hijleh, Nicolette Rigg, Erica Winterhelt, Meghan Kostashuk, Amber Monterio, Mandana Tavakolian, Nahieli Preciado Rivera, Benicio N Frey, Ram K Mishra, Todd Hoare
Journal: Journal of Controlled Release (2024)

While bipolar disorder patients can benefit from lithium therapy, high levels of lithium in the serum can induce undesirable systemic side effects. Intranasal (IN) lithium delivery offers a potential solution to this challenge given its potential to facilitate improved lithium transport to brain when delivered to the olfactory mucosa. Herein, a sprayable, in situ forming nanoparticle network hydrogel (NNH) based on Schiff base interactions between chelator-functionalized oxidized starch nanoparticles (SNPs) and carboxymethyl chitosan (CMCh) is reported that can be deployed within the nasal cavity to release ultra-small penetrative SNPs over time. Chelating functional groups including citrate, ethylenediaminetetraacetic acid, and pentetic acid are shown to bind a variety of cations including lithium, magnesium, and calcium, with chelation directly linked to enhancements in the gel mechanics even for monovalent lithium. The hydrogels show high in vitro cytocompatibility with mouse striatal neuron and human primary nasal cell lines. Effective IN delivery of lithium to the brain is demonstrated for the first time, with both solution-based and hydrogel-loaded lithium showing in vivo efficacy in an amphetamine-induced pre-clinical rat bipolar manic phase model; specifically, IN-delivered NNHs can maintain successful attenuation of locomotor activity for up to 6 h while all other tested treatments (drug-only IN or conventional intraperitoneal delivery) failed to retain attenuation for more than two hours at the same lithium dose. As such, in situ-gelling and ion-chelating NNHs represent a new material that can effectively enable metal ion management in biomedical applications.
Experience in Optimizing the Radiation Dose during Digital Mammography Using the CIRS 010D Phantom
Authors: T. V. Pavlova, O. A. Mitrohina, S. A. Varlamov
Journal: Radiology - Practice (2024)

Aim. Demonstrate the possibility of reducing the radiation load on the patient while maintaining high quality mammographic images. Materials and Methods. Using mammography, we obtained digital images of the breast phantom in various shooting modes, recording the dose load during the study and evaluating the quality of visualization. Results. The optimal shooting parameters have been determined at which the minimum radiation load is achieved without reducing the image quality. Conclusion. This study demonstrates the potential to reduce radiation exposure during mammography by optimizing the physical and technical parameters used in the procedure.
Masks of Pulmonary Thromboembolism on Chest Radiographs
Authors: M. Yu. Gaintsev, A. A. Speranskaya
Journal: Radiology - Practice (2024)

Aim. Assessment of detectability of pulmonary thromboembolism on radiographs. Identification of masks of pulmonary thromboembolism manifestations mimicking other diseases on radiographs. Materials and Methods. The retrospective analysis included 23 patients with pulmonary embolism proven by computed tomography, who were treated at the SBHI City Hospital No. 26. All patients underwent digital chest radiography in two projections on admission using a Samsung XGEO GC80 digital X-ray machine. Computed tomography was performed on a 128-slice General Electric Revolution EVO tomograph using intravenous bolus contrast with Omnipaque at a concentration of 300 mg iodine/ml. The findings of radiologists were compared with the data of computed tomography; detectability of pulmonary embolism on radiographs, correlation between the embolism massiveness and its manifestations on radiographs were evaluated. Results. Among the 23 digital radiographs interpreted, pulmonary thromboembolism was suspected in 1 case (detection rate of 4 %). In 8 cases (35 %) no abnormalities were found on radiographs. In three patients (13 %) findings were interpreted as manifestations of peripheral lung cancer, that turned out to be areas of pulmonary infarction on CT. The detection rate of indirect signs of pulmonary thromboembolism (discoid atelectasis, small hydrothorax, infarctions, pulmonary hypertension) was at least twice as high in the CT examination. No correlation between the massiveness of thromboembolism and its manifestations on radiographs has been revealed. The most frequent manifestations of pulmonary thromboembolism on radiographs were discoid atelectasis (35 %), lung infarction (35 %), small hydrothorax (26 %) and high position of the diaphragm on the affected side (22 %). Rare sign was dilatation of the pulmonary artery trunk (9 %). Conclusion. The detectability of pulmonary thromboembolism on digital radiographs is extremely low. Most often this diagnosis is hidden under the mask of a normal X-ray, tumour lesions or manifestations of cardiac insufficiency (hydrothorax). The lack of direct correlation between thromboembolism massiveness and lesions seen on radiographs requires the radiologist to be more attentive to clinical symptoms (sudden dyspnoea, chest pain, dry cough, etc.) when interpreting radiographs.
Criteria and Diagnostic Significance of Density Maps for Acute Lung Injury in Patients of the Intensive Care Unit According to Computed Tomography of the Chest
Authors: A. V. Bormyshev, T. G. Morozova
Journal: Radiology - Practice (2024)

Objective. To determine the criteria and diagnostic significance of density maps for acute lung injury (ALI) in patients of the intensive care unit according to computed tomography (CT) of the chest. Materials and Methods. 93 patients aged 44–85 years were examined in the Clinical Hospital No. 1, Smolensk from 2022 to 2024, men — 52 (55.9 %), women — 41 (44.1 %). Patients were admitted to the intensive care unit, 87 (95.6 %) of them were transferred to the other hospital departments corresponding to the nosological forms of the diseases; 81 (93.1 %) patients remained under follow up period during two years (inpatient and/or outpatient stages of treatment). All patients of the main group underwent CT of the chest, with additional assessment of lung tissue density maps, on a 64-slice GE Revolution EVO computed tomography scan, in the control group – in 19 (45.2 %) cases. Statistical analysis of the results included descriptive statistics, comparison samples of nonparametric criteria. Results. In our study with a summation quantitative criterion of lung tissue density maps of more than 14 %, we watched damage to all life support systems: kidney damage more often occurs with a density criterion from 14 to 25 %, then goes damage of central nervous system; in case of density criterion more than 26 % — kidneys and liver damage. In the monitoring in the intensive care unit in 57 patients, the summation quantitative criterion of density maps ranged from 14 to 25 %. In the follow up period of the presented group of patients, a high correlation was noted with negative clinical and laboratory dynamics in the form of shortness of breath, cyanosis, tachypnea, a decrease in partial oxygen pressure in arterial blood and the development of ALI (r = 0.978). The summation quantitative criterion of lung tissue density maps made it possible to predict the most likely changes from other life support systems upon admission (AUROC 0.912; CI 0.881–0.919) and follow up period (AUROC 0.902; CI 0.868–0.907). Conclusions There was a high correlation between negative clinical and laboratory dynamics and the development of ALI with a summation quantitative criterion of lung tissue density maps according to CT from 14 to 25 % (r = 0.978), as well as the progression of ALI at 26 % (r = 0.985). The summation quantitative criterion of lung tissue density maps based on CT allows predicting changes from other life support systems upon admission (AUROC 0.912; CI 0.881–0.919) and follow up period (AUROC 0.902; CI 0.868 – 0.907). The inclusion in the algorithm of management of patients in the intensive care unit of the assessment of lung tissue density maps in CT of the chest helps to reduce mortality and the risk of developing the syndrome of the consequences of intensive therapy.
Review of Physicotechnical and Functional Scanning Parameters on Modern Cone-Beam Computed Tomographs
Authors: N. Yu. Pereverzev, N. N. Blinov, E. G. Gorlycheva
Journal: Radiology - Practice (2024)

Relevance. Cone beam computed tomography (CBCT) is widely used in dentistry and other fields of medicine due to the high image quality and low radiation load. Advanced models of tomographs allow for studies of various anatomical areas, which emphasizes the importance of understanding changes in their physical and technical characteristics for an optimal ratio between image quality and radiation load. Review. The article analyzes the physical, technical and functional parameters of scanning various modern cone-beam computed tomographs (CBCT), which are available in the public domain — central printing or presented on the official websites of manufacturers. As part of the study, data were collected and analyzed on the physical, technical and functional parameters of 11 cone-beam tomographs from various manufacturers equipped with a tomographic table or having the possibility of retrofitting with a tomographic table for conducting research with the positioning of the object of study in a horizontal position. The data obtained were compared with the parameters of cone-beam tomographs used to study the maxillofacial region. Conclusions. The design features of the new generation of cone beam tomographs increase the variability of functionality, contributing to the expansion of the range of diagnostic techniques. There is no information in open sources about the distances between the emitter and the detector, as well as the object-detector distance, which makes it impossible to draw conclusions about the mechanical and physical solutions in cone beam tomographs, which significantly affects the quality of the images obtained.
Long-Term Self-Administered Outpatient Parenteral Antimicrobial Therapy in the Treatment of Tuberculosis
Authors: A. Rauch, N. Köhler, T. T. Brehm, N. Zielinski, K. Stoycheva, C. Maier, L. Böttcher, I. Friesen, D. Schaub, M. Reimann, S. Schmiedel, C. Lange, B. Kalsdorf
Journal: Drugs (2024)

To investigate the safety profiles and clinical outcomes in a continuous cohort of tuberculosis (TB) patients from a clinical referral centre in Germany receiving self-administered outpatient parenteral antimicrobial therapy (sOPAT).
Identifying proteins and pathways associated with multimorbidity in 53,026 adults
Authors: Yi-Lin Chen, Jia You, Yu Guo, Yi Zhang, Bing-Ran Yao, Ji-Jing Wang, Shi-Dong Chen, Yi-Jun Ge, Liu Yang, Xin-Rui Wu, Bang-Sheng Wu, Ya-Ru Zhang, Qiang Dong, Jian-Feng Feng, Mei Tian, Wei Cheng, Jin-Tai Yu
Journal: Metabolism (2024)
Hypothalamic SIRT1-mediated regulation of the hormonal trigger of ovulation and its repression in energy deficit
Authors: María J Vazquez, Silvia Daza-Dueñas, Inmaculada Velasco, Francisco Ruiz-Pino, María J Sanchez-Tapia, María Manfredi-Lozano, Carmen Torres-Granados, Alexia Barroso, Juan Roa, Miguel A Sánchez-Garrido, Carlos Dieguez, Alejandro Lomniczi, Rubén Nogueiras, Manuel Tena-Sempere
Journal: Metabolism (2024)

Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of Kiss1, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express Sirt1 mRNA. Reciprocal changes in hypothalamic SIRT1 content and Kiss1 expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced Kiss1 expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.