tbuckley/cabot-search huggingface dataset:
Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum (Solvent Front Mutation [G2032R] and Central β-Sheet 6 [Cβ6] Mutation [L2086F])
Authors: Sai-Hong Ignatius Ou, Garo G. Hagopian, Shannon S. Zhang, Misako Nagasaka
Journal: Journal of Thoracic Oncology (2023)

Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib. Here, we categorized ROS1 TKIs by their structures (cyclic versus noncyclic) and inhibitory abilities (active against solvent front mutation G2032R or central β-sheet #6 [Cβ6] mutation L2086F) and summarized their reported clinical activity in order to provide a dashboard on how to use these ROS1 TKIs in various clinical situations. In addition, the less known Cβ6 mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (repotrectinib, taletrectinib, and potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and potentially by certain L-shaped type I ROS1 TKIs including ceritinib and gilteritinib, which is approved as a FLT3 inhibitor for relapsed refractory FLT3+ acute myeloid leukemia but have published preclinical activites against ROS1 (and ALK). Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target ROS1 L2086F Cβ6 mutation.
Adult dental epithelial stem cell-derived organoids deposit hydroxylapatite biomineral
Authors: Hyun-Yi Kim, Victoria Cooley, Eun-Jung Kim, Shujin Li, Jong-Min Lee, Dina Sheyfer, Wenjun Liu, Ophir D. Klein, Derk Joester, Han-Sung Jung
Journal: International Journal of Oral Science (2023)

Abstract Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. The unique function of the epithelial cells synthesizing crystallites and assembling them in a mechanically robust structure is not fully elucidated yet, partly due to limitations with in vitro experimental models. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When transplanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model to study mineralization process by dental epithelium, which can pave the way to understanding amelogenesis and developing regenerative therapy of enamel.
Novel data-driven subtypes and stages of brain atrophy in the ALS–FTD spectrum
Authors: Ting Shen, Jacob W. Vogel, Jeffrey Duda, Jeffrey S. Phillips, Philip A. Cook, James Gee, Lauren Elman, Colin Quinn, Defne A. Amado, Michael Baer, Lauren Massimo, Murray Grossman, David J. Irwin, Corey T. McMillan
Journal: Translational Neurodegeneration (2023)

Abstract Background TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS–FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS–FTD spectrum. Methods We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS–FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS–FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease. Results SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS–FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King’s stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology. Conclusions Our findings suggest distinct neurodegenerative subtypes of disease along the ALS–FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
Biatrial myopathy in heart failure with preserved ejection fraction
Authors: Kazunori Omote, Hidemi Sorimachi, Masaru Obokata, Frederik H. Verbrugge, Massar Omar, Dejana Popovic, Yogesh N.V. Reddy, Sorin V. Pislaru, Patricia A. Pellikka, Barry A. Borlaug
Journal: European Journal of Heart Failure (2023)
Updated Prevalence of Lymphangioleiomyomatosis in Europe
Authors: Evelyn Lynn, Sarah H. Forde, Alessandro N. Franciosi, Elisabeth Bendstrup, Marcel Veltkamp, Anne E. Wind, Coline H. M. Van Moorsel, Thomas Kromann Lund, Michael Thomas Durheim, Evelien F. H. I. Peeters, Michael P. Keane, Cormac McCarthy, Marissa O’Callaghan, Amina Jouida, Adriane D. M. Vorselaars, Michael Perch
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Updated Prevalence of Lymphangioleiomyomatosis in Europe." American Journal of Respiratory and Critical Care Medicine, 209(4), pp. 456–459
<scp>Poly‐Refractory</scp> Rheumatoid Arthritis: An Uncommon Subset of Difficult to Treat Disease With Distinct Inflammatory and Noninflammatory Phenotypes
Authors: Paula David, Andrea Di Matteo, Or Hen, Shouvik Dass, Helena Marzo‐Ortega, Richard J. Wakefield, Leslie‐Anne Bissell, Jacqueline Nam, Kulveer Mankia, Paul Emery, Benazir Saleem, Dennis McGonagle
Journal: Arthritis & Rheumatology (2023)

Objective To investigate the prevalence of poly‐refractory rheumatoid arthritis (RA) defined as failure of all biological (b)/targeted synthetic (ts)‐disease‐modifying drugs (DMARDs). To further investigate whether patients with persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA), determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult‐to‐treat RA (D2T‐RA) and poly‐refractory RA groups. Methods A cross‐sectional study of 1,591 patients with RA on b/tsDMARDs that evaluated D2T‐RA criteria and subclassified as poly‐refractory if inefficacy/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in one or more swollen joint and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly‐refractory, PIRRA, and NIRRA phenotypes. Results 122 of 1,591 were excluded due to missing data. 247 of 1,469 (16.8%) had D2T‐RA and only 40 of 1,469 (2.7%) poly‐refractory RA. This latter group had higher disease activity score 28 C‐reactive protein (CRP) (median 5.4 vs 5.02, P &lt; 0.05), CRP levels (median 13 vs 5 mg/l, P &lt; 0.01), and smoking (ever) rates (20% vs 4%, P &lt; 0.01) compared with other D2T patients. Smoking was associated with poly‐refractory RA (odds ratio 5.067, 95% CI 1.774–14.472, P = 0.002). Of 107 patients with D2T‐RA with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. Patients with NIRRA had elevated body mass index (median 30 vs 26, P &lt; 0.001) and higher fibromyalgia prevalence (15% vs 3%, P &lt; 0.05), lower swollen joint count (median: 2 vs 5, P &lt; 0.001), and lower CRP levels (5 vs 10, P &lt; 0.01). Conclusion Only 2.7% of D2T‐RA failed all classes of b/tsDMARDs. Among D2T‐RA, less than 60% had objective signs of inflammation, representing a target for innovative strategies. image
Disentangling the age-related manner in the associations between gut microbiome and women’s health: a multi-cohort microbiome study
Authors: Chao Dong, Quanquan Guan, Wei Xu, Xiaochen Zhang, Bowen Jin, Shumin Yu, Xiaoyu Xu, Yankai Xia
Journal: Gut Microbes (2023)

Women's health encompasses life-course healthcare, and mounting evidence emphasizes the pivotal contribution of gut microbiota. Therefore, understanding the temporal dynamics of gut microbiota and how age influences disease-gut microbiota associations is essential for improving women's health. By analyzing metagenomic data from 3625 healthy women, we revealed significant effects of age on gut microbiota and age-dependent patterns in microbial features, such as relative abundance, Shannon index, and microbial network properties. Additionally, declining trends in the predictive accuracy of gut microbiota for age groups were shown using iterative sub-sampling based random forest (ISSRF) model. Age-specific species markers were also identified, many of which were shared across age groups. To investigate the influence of age on disease-gut microbiota associations, metagenomic data from 681 women with various disease conditions and 491 matched healthy controls were collected. A substantial proportion of species markers for inflammatory bowel disease (IBD), type 2 diabetes (T2D), atherosclerotic cardiovascular disease (ACVD), and impaired glucose tolerance (IGT) differed in relative abundance across age groups, and were also age-specific species markers. Besides, the microbiota-based probabilities of IBD and ACVD were positively correlated with age. Furthermore, the age specificity of disease-gut microbiota associations was explored using the ISSRF model. Associations between IBD and gut microbiota were age-specific, with reduced stability of disease species markers in childhood and adolescence, possibly due to decrease in the effect size between patients and controls. Our findings provided valuable insights into promoting healthy aging and developing personalized healthcare strategies for women.
Evolution of <i>E. coli</i> in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance
Authors: Rahul Unni, Nadia Andrea Andreani, Marie Vallier, Silke S. Heinzmann, Jan Taubenheim, Martina A. Guggeis, Florian Tran, Olga Vogler, Sven Künzel, Jan-Bernd Hövener, Philip Rosenstiel, Christoph Kaleta, Astrid Dempfle, Daniel Unterweger, John F. Baines
Journal: Gut Microbes (2023)

Inflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.
Clinical Features and Immunogenetic Risk Factors Associated With Additional Autoantibodies in Anti‐Transcriptional Intermediary Factor 1γ <scp>Juvenile‐Onset</scp> Dermatomyositis
Authors: Matthew A. Sherman, Qingyuan Yang, Laura Gutierrez‐Alamillo, Katherine Pak, Willy A. Flegel, Andrew L. Mammen, Lisa G. Rider, Livia A. Casciola‐Rosen
Journal: Arthritis & Rheumatology (2023)

Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile-onset DM (JDM) and to determine their associated features.
Global Burden of Chronic Obstructive Pulmonary Disease Through 2050
Authors: Elroy Boers, Meredith Barrett, Jason G. Su, Adam V. Benjafield, Sanjeev Sinha, Leanne Kaye, Heather J. Zar, Vy Vuong, Daniela Tellez, Rahul Gondalia, Mary B. Rice, Carlos M. Nunez, Jadwiga A. Wedzicha, Atul Malhotra
Journal: JAMA Network Open (2023)

Importance Chronic obstructive pulmonary disease (COPD) is a respiratory condition that is associated with significant health and economic burden worldwide. Previous studies assessed the global current-day prevalence of COPD, but to better facilitate resource planning and intervention development, long-term projections are needed. Objective To assess the global burden of COPD through 2050, considering COPD risk factors. Design, Setting, and Participants In this modeling study, historical data on COPD prevalence was extracted from a recent meta-analysis on 2019 global COPD prevalence, and 2010 to 2018 historical prevalence was estimated using random-effects meta-analytical models. COPD risk factor data were obtained from the Global Burden of Disease database. Main Outcomes and Measures To project global COPD prevalence to 2050, generalized additive models were developed, including smoking prevalence, indoor and outdoor air pollution, and development indices as predictors, and stratified by age, sex, and World Bank region. Results The models estimated that the number of COPD cases globally among those aged 25 years and older will increase by 23% from 2020 to 2050, approaching 600 million patients with COPD globally by 2050. Growth in the burden of COPD was projected to be the largest among women and in low- and middle-income regions. The number of female cases was projected to increase by 47.1% (vs a 9.4% increase for males), and the number of cases in low- and middle-income regions was expected to be more than double that of high-income regions by 2050. Conclusions and Relevance In this modeling study of future COPD burden, projections indicated that COPD would continue to affect hundreds of millions of people globally, with disproportionate growth among females and in low-middle income regions through 2050. Further research, prevention, and advocacy are needed to address these issues so that adequate preparation and resource allocation can take place.
Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA
Authors: Reshma Jagsi, Kent A. Griffith, Eleanor E. Harris, Jean L. Wright, Abram Recht, Alphonse G. Taghian, Lucille Lee, Meena S. Moran, William Small, Candice Johnstone, Asal Rahimi, Gary Freedman, Mahvish Muzaffar, Bruce Haffty, Kathleen Horst, Simon N. Powell, Jody Sharp, Michael Sabel, Anne Schott, Mahmoud El-Tamer
Journal: Journal of Clinical Oncology (2023)

PURPOSE Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor–positive, progesterone receptor–positive, and human epidermal growth factor receptor 2–negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer–specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.
Exudate‐Induced Gelatinizable Nanofiber Membrane with High Exudate Absorption and Super Bactericidal Capacity for Bacteria‐Infected Wound Management
Authors: Wenjie Wang, Qiao Yu, Zijian Shao, Yuxuan Guo, Yilin Wang, Ye Yang, Weifeng Zhao, Changsheng Zhao
Journal: Advanced Healthcare Materials (2023)

Abstract Invasion of bacteria and continuous oozing of exudate are significant causes of interference with the healing of infected wounds. Therefore, an exudate‐induced gelatinizable and near‐infrared (NIR)‐responsive nanofiber membrane composed of polyvinyl alcohol (PVA), carboxymethyl chitosan (CMC), and Fe‐doped phosphomolybdic acid (Fe‐PMA) with exceptional exudate absorption capacity and potent bactericidal efficacy is developed and denoted as the PVA‐FP‐CMC membrane. After absorbing exudate, the fiber membrane can transform into a hydrogel membrane, forming coordination bonds between the Fe‐PMA and CMC. The unique exudate‐induced gelation process imparts the membrane with high exudate absorption and retention capability, and the formed hydrogel also traps the bacteria that thrive in the exudate. Moreover, it is discovered for the first time that the Fe‐PMA exhibits an enhanced photothermal conversion capability and photocatalytic activity compared to the PMA. Therefore, the presence of Fe‐PMA provides the membrane with a photothermal and photodynamic therapeutic effect for killing bacteria. The PVA‐FP‐CMC membrane is proven with a liquid absorption ratio of 520.7%, a light‐heat conversion efficiency of 41.9%, high‐level generation of hydroxyl radical (•OH) and singlet oxygen ( 1 O 2 ), and a bacterial killing ratio of 100% for S. aureus and 99.6% for E. coli . The treatment of infected wounds on the backs of rats further confirms the promotion of wound healing by the PVA‐FP‐CMC membrane with NIR irradiation. Overall, this novel functional dressing for the synergistic management of bacteria‐infected wounds presents a promising therapeutic strategy for tissue repair and regeneration.
Risks of depression, anxiety, and suicide in partners of men with prostate cancer: a national cohort study
Authors: Casey Crump, Pär Stattin, James D Brooks, Jan Sundquist, Alexis C Edwards, Kristina Sundquist, Weiva Sieh
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background A diagnosis of prostate cancer (PC) may cause psychosocial distress not only in a man but also in his intimate partner. However, long-term risks of depression, anxiety, or suicide in partners of men with PC are largely unknown. Methods A national cohort study was conducted of 121 530 partners of men diagnosed with PC during 1998-2017 and 1 093 304 population-based controls in Sweden. Major depression, anxiety disorder, and suicide death were ascertained through 2018. Cox regression was used to compute hazard ratios (HRs) while adjusting for sociodemographic factors. Results Partners of men with high-risk PC had increased risks of major depression (adjusted HR = 1.34, 95% confidence interval [CI] = 1.30 to 1.39) and anxiety disorder (adjusted HR = 1.25, 95% CI = 1.20 to 1.30), which remained elevated 10 or more years later. Suicide death was increased in partners of men with distant metastases (adjusted HR = 2.38, 95% CI = 1.08 to 5.22) but not other high-risk PC (adjusted HR =1.14, 95% CI = 0.70 to 1.88). Among partners of men with high-risk PC, risks of major depression and anxiety disorder were highest among those 80 years of age or older (adjusted HR = 1.73; 95% CI = 1.53 to 1.96; adjusted HR = 1.70, 95% CI = 1.47 to 1.96, respectively), whereas suicide death was highest among those younger than 60 years of age (adjusted HR = 7.55, 95% CI = 2.20 to 25.89). In contrast, partners of men with low- or intermediate-risk PC had modestly or no increased risks of these outcomes. Conclusions In this large cohort, partners of men with high-risk PC had increased risks of major depression and anxiety disorder, which persisted for 10 or more years. Suicide death was increased 2-fold in partners of men with distant metastases. Partners as well as men with PC need psychosocial support and close follow-up for psychosocial distress.
Risk of readmission and death after hospitalization for worsening heart failure: Role of post‐discharge follow‐up visits in a real‐world study from the <scp>Grand Est</scp> Region of <scp>France</scp>
Authors: Guillaume Baudry, Ouarda Pereira, Kévin Duarte, João Pedro Ferreira, Gianluigi Savarese, Adeline Welter, Philippe Tangre, Zohra Lamiral, Nelly Agrinier, Nicolas Girerd
Journal: European Journal of Heart Failure (2023)

Patients who experience hospitalizations due to heart failure (HF) face a significant risk of readmission and mortality. Our objective was to evaluate whether the risk of hospitalization and mortality following discharge from HF hospitalization differed based on adherence to the outpatient follow-up (FU) protocol comprising an appointment with a general practitioner (GP) within 15 days, a cardiologist within 2 months or both (termed combined FU).