tbuckley/cabot-search huggingface dataset:
The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases
Authors: Arazu Sharif, John Mamo, Virginie Lam, Hani Al-Salami, Armin Mooranian, Gerald F. Watts, Roger Clarnette, Giuseppe Luna, Ryu Takechi
Journal: Translational Neurodegeneration (2024)

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.
Concomitant Medications for Progressive Supranuclear Palsy
Authors: Jay M. Iyer, Douglas Gunzler, Anthony E. Lang, Lawrence I. Golbe, Alexander Pantelyat, Adam L. Boxer, Anne-Marie Wills
Journal: JAMA Neurology (2024)

This secondary analysis of a randomized clinical trial examines changes in the progression of progressive supranuclear palsy (PSP) associated with 31 concomitant medication classes used by study participants over 1 year.
Concurrent Circulating Tumor DNA and Tissue Genotyping—Ready for Prime Time?
Authors: Benjamin A. Bleiberg, Charu Aggarwal
Journal: JAMA Network Open (2024)

Wade T. Iams, MD; Matthew Mackay, PhD; Rotem Ben-Shachar, PhD; Joshua Drews, MS; Kabir Manghnani, BS; Adam J. Hockenberry, PhD; Massimo Cristofanilli, MD; Halla Nimeiri, MD; Justin Guinney, PhD; Al B. Benson III, MD
Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue
Authors: Lucas Jurado-Fasoli, Guillermo Sanchez-Delgado, Xinyu Di, Wei Yang, Isabelle Kohler, Francesc Villarroya, Concepcion M. Aguilera, Thomas Hankemeier, Jonatan R. Ruiz, Borja Martinez-Tellez
Journal: Cell Reports Medicine (2024)

Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.
Effect of Acupuncture vs Sham Acupuncture on Patients With Poststroke Motor Aphasia
Authors: Boxuan Li, Shizhe Deng, Bifang Zhuo, Bomo Sang, Junjie Chen, Menglong Zhang, Guang Tian, Lili Zhang, Yuzheng Du, Peng Zheng, Gonglei Yue, Zhihong Meng
Journal: JAMA Network Open (2024)

Importance Motor aphasia is common among patients with stroke. Acupuncture is recommended as an alternative therapy for poststroke aphasia, but its efficacy remains uncertain. Objective To investigate the effects of acupuncture on language function, neurological function, and quality of life in patients with poststroke motor aphasia. Design, Setting, and Participants This multicenter, sham-controlled, randomized clinical trial was conducted in 3 tertiary hospitals in China from October 21, 2019, to November 13, 2021. Adult patients with poststroke motor aphasia were enrolled. Data analysis was performed from February to April 2023. Interventions Eligible participants were randomly allocated (1:1) to manual acupuncture (MA) or sham acupuncture (SA) groups. Both groups underwent language training and conventional treatments. Main Outcomes and Measures The primary outcomes were the aphasia quotient (AQ) of the Western Aphasia Battery (WAB) and scores on the Chinese Functional Communication Profile (CFCP) at 6 weeks. Secondary outcomes included WAB subitems, Boston Diagnostic Aphasia Examination, National Institutes of Health Stroke Scale, Stroke-Specific Quality of Life Scale, Stroke and Aphasia Quality of Life Scale–39, and Health Scale of Traditional Chinese Medicine scores at 6 weeks and 6 months after onset. All statistical analyses were performed according to the intention-to-treat principle. Results Among 252 randomized patients (198 men [78.6%]; mean [SD] age, 60.7 [7.5] years), 231 were included in the modified intention-to-treat analysis (115 in the MA group and 116 in the SA group). Compared with the SA group, the MA group had significant increases in AQ (difference, 7.99 points; 95% CI, 3.42-12.55 points; P = .001) and CFCP (difference, 23.51 points; 95% CI, 11.10-35.93 points; P &amp;amp;lt; .001) scores at week 6 and showed significant improvements in AQ (difference, 10.34; 95% CI, 5.75-14.93; P &amp;amp;lt; .001) and CFCP (difference, 27.43; 95% CI, 14.75-40.10; P &amp;amp;lt; .001) scores at the end of follow-up. Conclusions and Relevance In this randomized clinical trial, patients with poststroke motor aphasia who received 6 weeks of MA compared with those who received SA demonstrated statistically significant improvements in language function, quality of life, and neurological impairment from week 6 of treatment to the end of follow-up at 6 months after onset. Trial Registration Chinese Clinical Trial Registry: ChiCTR1900026740
Error in Key Points
Journal: JAMA Pediatrics (2024)

Midori Yamamoto, PhD; Hidetoshi Mezawa, MD, PhD; Kenichi Sakurai, MD, PhD; Chisato Mori, MD, PhD; Japan Environment and Children’s Study Group; Michihiro Kamijima; Shin Yamazaki ; Yukihiro Ohya ; Reiko Kishi ; Nobuo Yaegashi ; Koichi Hashimoto ; Chisato Mori ; Shuichi Ito; Zentaro Yamagata ; Hidekuni Inadera ; Takeo Nakayama ; Tomotaka Sobue ; Masayuki Shima ; Seiji Kageyama ; Narufumi Suganuma ; Shoichi Ohga ; Takahiko Katoh
Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit
Authors: Joanna L. Stollings, Christina S. Boncyk, Caroline I. Birdrow, Wencong Chen, Rameela Raman, Deepak K. Gupta, Dan M. Roden, Erika L. Rivera, Amelia W. Maiga, Shayan Rakhit, Pratik P. Pandharipande, E. Wesley Ely, Timothy D. Girard, Mayur B. Patel
Journal: JAMA Network Open (2024)

Importance Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, −1.0 (IQR, −28.0 to 15.0) ms; ziprasidone, 0 (IQR, −23.0 to 20.0) ms; and placebo, −3.5 (IQR, −24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex ( P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration ClinicalTrials.gov Identifier: NCT01211522
Unveiling Liquid Gold: Lymph as an HPV Marker in OPSCC to guide treatment decisions
Authors: Nicholas B. Shannon, N. Gopalakrishna Iyer
Journal: Clinical Cancer Research (2024)

Summary Distinguishing low- versus high-risk HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is pivotal for tailoring treatment. Liquid biopsy, measuring cell-free HPV-DNA in serum and saliva, assesses treatment response and early-recurrence risk. Postoperative lymphatic fluid may better guide future adjuvant therapy decisions due to its proximity to primary lesions and lymph nodes. See related article by Earland et al., p. 1409
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Authors: Bilal Khalil, Miriam Linsenmeier, Courtney L. Smith, James Shorter, Wilfried Rossoll
Journal: Molecular Neurodegeneration (2024)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.
From Serendipity to Intention: Development of Brain-Penetrant PARP1-Selective Inhibitors
Authors: Filipa Lynce, Nancy U. Lin
Journal: Clinical Cancer Research (2024)

Summary Primary and secondary brain tumors cause significant mortality and constitute an important unmet need. The development of AZD9574, a brain-penetrant, PARP1-selective inhibitor with favorable pharmacologic properties and intriguing preclinical activity, has led to an ongoing clinical trial evaluating it alone and in combination with temozolomide or antibody drug conjugates. See related article by Staniszewska et al., p. 1338
BTK Inhibitors in CLL/SLL: The Landscape 10 Years Out
Journal: Cancer Discovery (2024)

The BTK-targeting arsenal for chronic lymphocytic leukemia or small lymphocytic lymphoma continues to expand, with a noncovalent inhibitor, pirtobrutinib, now an approved later-line option. As well, a fourth-generation candidate, LP-168, which is both irreversible/reversible, has shown preliminary phase I efficacy. BTK inhibitors have limited utility on their own, however; to combat resistance and achieve durable remissions, the field is looking toward multidrug combinations, including with potentially disease-eradicating CAR T-cell therapy.
On-chip recapitulation of the tumor microenvironment: A decade of progress
Authors: S.M. Giannitelli, V. Peluzzi, S. Raniolo, G. Roscilli, M. Trombetta, P. Mozetic, A. Rainer
Journal: Biomaterials (2024)

One of the hurdles to the development of new anticancer therapies is the lack of in vitro models which faithfully reproduce the in vivo tumor microenvironment (TME). Understanding the dynamic relationships between the components of the TME in a controllable, scalable, and reliable setting would indeed support the discovery of biological targets impacting cancer diagnosis and therapy. Cancer research is increasingly shifting from traditional two-dimensional (2D) cell culture toward three-dimensional (3D) culture models, which have been demonstrated to increase the significance and predictive value of in vitro data. In this scenario, microphysiological systems (also known as Organs-on-Chip) have emerged as a relevant technological platform enabling more predictive investigation of cell-cell and cell-ECM interplay in cancer, attracting a significant research effort in the last years. This review illustrates one decade of progress in the field of tumor-microenvironment-on-chip (TMOC) approaches, exploiting either cell-laden microfluidic chambers or microfluidic confined tumor spheroids to model the TME. TMOCs have been designed to recapitulate several aspects of the TME, including tumor cells, the tumor-associated stroma, the immune system, and the vascular component. Significantly, the last aspect has emerged for its pivotal role in orchestrating cellular interactions and modulating drug pharmacokinetics on-chip. A further advancement has been represented by integration of TMOCs into multi-organ microphysiological systems, with the final aim to follow the metastatic cascade to target organs and to study the effects of chemotherapies at a systemic level. We highlight that the increased degree of complexity achieved by the most advanced TMOC models has enabled scientists to shed new light on the role of microenvironmental factors in tumor progression, metastatic cascade, and response to drugs.
Obstetrics and Gynecology residency training in transgender care: a national survey of residents and program directors
Authors: Amanda S. Lee Cruz, Elisa Lee, Joshua Soler, Pamela Sheffler, Sarah E. Knapp, Sadikah Behbehani
Journal: International Journal of Transgender Health (2024)

Aim: Obstetricians and gynecologists (OB-GYN) routinely care for transgender patients though most OB-GYN practitioners do not have any transgender care-specific training. The pervasive lack of training and education leads to dire health consequences for transgender patients. Residents and program directors within U.S. OB-GYN residency programs have been surveyed separately. To our knowledge, this is the first study that compares responses from residents and program directors related to their training. Our study aims to assess OB-GYN residents' and program directors' levels of comfort, preparedness, and knowledge in caring for transgender patients.
“It’s just a general lack of awareness, that breeds a sense that there isn’t space to talk about our needs”: barriers and facilitators experienced by transgender people accessing healthcare in Aotearoa/New Zealand
Authors: Sofía González, Jaimie F. Veale
Journal: International Journal of Transgender Health (2024)

Introduction Transgender people face serious health disparities associated with underlying social determinants, such as unmet healthcare needs and negative experiences with healthcare providers. Healthcare accessibility dimensions include availability, approachability, acceptability, affordability, and appropriateness. This study aimed to identify the perceived barriers and facilitators that transgender people in Aotearoa/New Zealand experience within these dimensions, as few studies have explored multiple dimensions of healthcare access for transgender people using a large national sample.
Diagnostic performance of artificial intelligence-assisted PET imaging for Parkinson’s disease: a systematic review and meta-analysis
Authors: Jing Wang, Le Xue, Jiehui Jiang, Fengtao Liu, Ping Wu, Jiaying Lu, Huiwei Zhang, Weiqi Bao, Qian Xu, Zizhao Ju, Li Chen, Fangyang Jiao, Huamei Lin, Jingjie Ge, Chuantao Zuo, Mei Tian
Journal: npj Digital Medicine (2024)

Abstract Artificial intelligence (AI)-assisted PET imaging is emerging as a promising tool for the diagnosis of Parkinson’s disease (PD). We aim to systematically review the diagnostic accuracy of AI-assisted PET in detecting PD. The Ovid MEDLINE, Ovid Embase, Web of Science, and IEEE Xplore databases were systematically searched for related studies that developed an AI algorithm in PET imaging for diagnostic performance from PD and were published by August 17, 2023. Binary diagnostic accuracy data were extracted for meta-analysis to derive outcomes of interest: area under the curve (AUC). 23 eligible studies provided sufficient data to construct contingency tables that allowed the calculation of diagnostic accuracy. Specifically, 11 studies were identified that distinguished PD from normal control, with a pooled AUC of 0.96 (95% CI: 0.94–0.97) for presynaptic dopamine (DA) and 0.90 (95% CI: 0.87–0.93) for glucose metabolism ( 18 F-FDG). 13 studies were identified that distinguished PD from the atypical parkinsonism (AP), with a pooled AUC of 0.93 (95% CI: 0.91 − 0.95) for presynaptic DA, 0.79 (95% CI: 0.75–0.82) for postsynaptic DA, and 0.97 (95% CI: 0.96–0.99) for 18 F-FDG. Acceptable diagnostic performance of PD with AI algorithms-assisted PET imaging was highlighted across the subgroups. More rigorous reporting standards that take into account the unique challenges of AI research could improve future studies.
Structural variation and DNA methylation shape the centromere-proximal meiotic crossover landscape in Arabidopsis
Authors: Joiselle B. Fernandes, Matthew Naish, Qichao Lian, Robin Burns, Andrew J. Tock, Fernando A. Rabanal, Piotr Wlodzimierz, Anette Habring, Robert E. Nicholas, Detlef Weigel, Raphael Mercier, Ian R. Henderson
Journal: Genome biology (2024)

Centromeres load kinetochore complexes onto chromosomes, which mediate spindle attachment and allow segregation during cell division. Although centromeres perform a conserved cellular function, their underlying DNA sequences are highly divergent within and between species. Despite variability in DNA sequence, centromeres are also universally suppressed for meiotic crossover recombination, across eukaryotes. However, the genetic and epigenetic factors responsible for suppression of centromeric crossovers remain to be completely defined.
Using digital technologies to diagnose in the home: recommendations from a Delphi panel
Authors: David A. Simon, Sara Raza, Carmel Shachar, I. Glenn Cohen
Journal: npj Digital Medicine (2024)

Abstract Rapid advances in digital technology have expanded the availability of diagnostic tools beyond traditional medical settings. Previously confined to clinical environments, these many diagnostic capabilities are now accessible outside the clinic. This study utilized the Delphi method, a consensus-building approach, to develop recommendations for the development and deployment of these innovative technologies. The study findings present the 29 consensus-based recommendations generated through the Delphi process, providing valuable insights and guidance for stakeholders involved in the implementation and utilization of these novel diagnostic solutions. These recommendations serve as a roadmap for navigating the complexities of integrating digital diagnostics into healthcare practice outside traditional settings like hospitals and clinics.
Lumasiran: A Review in Primary Hyperoxaluria Type 1
Authors: Connie Kang
Journal: Drugs (2024)

Lumasiran (Oxlumo®), a first-in-class synthetic, double-stranded, ribonucleic acid (RNA) interference molecule targeting glycolate oxidase through silencing HAO1 mRNA, is approved in several countries for patients of any age and stage of kidney function with primary hyperoxaluria type 1 (PH1). Approval was based on results from the phase III ILLUMINATE trials. In the double-blind, placebo-controlled, ILLUMINATE-A trial, subcutaneous lumasiran was significantly more effective than placebo in reducing 24-h urinary oxalate excretion in patients aged ≥ 6 years with PH1; this effect was sustained for ≥ 36 months in ongoing longer-term analyses. In the single-arm ILLUMINATE-B trial, lumasiran reduced urinary oxalate:creatinine ratios and plasma oxalate levels in patients aged < 6 years with PH1. In the single-arm ILLUMINATE-C trial, lumasiran reduced plasma oxalate levels in patients with PH1 receiving dialysis as well as those not receiving dialysis. In secondary and exploratory analyses of these trials, nephrocalcinosis grade, kidney stone event rates and estimated glomerular filtration rates were either stable or improved with lumasiran. Lumasiran had an acceptable tolerability profile that remained consistent in longer-term analyses; the most common adverse events were mild and transient injection-site reactions. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1. Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that leads to excess oxalate in urine or plasma requiring removal by the kidneys. This overproduction is damaging and can lead to kidney failure. Management of PH1 is typically not curative, eventually ending in kidney and/or liver transplantation. Lumasiran (Oxlumo®) is the first medicine to be approved in several countries for use in patients with PH1, regardless of their age or level of kidney function. It reduces liver oxalate production, lessening damage to the kidneys and potentially reducing the need for organ transplantation. In clinical trials, lumasiran was effective in reducing oxalate levels (in urine and/or plasma) in patients of all ages with PH1, and irrespective of whether they were receiving dialysis or not. Lumasiran either improved or stabilized the severity of calcium deposition in the kidneys, number of kidney stone events and kidney function. Lumasiran had an acceptable tolerability profile; the most common side effects were mild injection-site reactions that resolved quickly. Thus, lumasiran is an effective treatment option, with an acceptable tolerability profile, in patients with PH1.