tbuckley/cabot-search huggingface dataset:
Determinants of Diabetes Awareness Among Hispanic/Latino Adults in the U.S., 2005–2018
Authors: Jessica Niño de Rivera, Sandra S. Albrecht
Journal: Diabetes Care (2024)

OBJECTIVE Despite improvements in screening, Hispanics/Latinos bear a disproportionate burden of undiagnosed diabetes in the U.S. Identifying who is at risk within this large and diverse population is important for targeting interventions. In this study, we sought to characterize risk factors for undiagnosed diabetes among Hispanics/Latinos. We also investigated determinants among insured adults to explore barriers for those with access to care. RESEARCH DESIGN AND METHODS We used data from 1,883 Hispanic/Latino adults aged ≥20 years from the National Health and Nutrition Examination Surveys (2005–2018). Sequential multivariable logistic regression models were used to examine a range of social, health care, and individual-level determinants of undiagnosed diabetes (defined as having elevated fasting plasma glucose ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol) in participants self-reporting as not having diabetes) in the overall sample and among those with health insurance (n = 1,401). RESULTS Younger age (20–44 years), male sex, and having immigrated (compared with being U.S. born), but not socioeconomic factors, were significantly associated with a higher odds of undiagnosed diabetes compared with being diagnosed. These estimates were attenuated after adjusting for health care utilization variables. In fully adjusted models, having no health care visits in the past year, reporting no family history of diabetes, and having better self-reported health were the predominant risk factors for undiagnosed diabetes in the overall sample and among insured Hispanic/Latino adults. CONCLUSIONS Our findings highlight the importance of reaching younger, male, and immigrant Hispanic/Latino adults and addressing barriers to health care utilization, even among insured adults, to improve diabetes awareness.
Low circulating tumor cell levels correlate with favorable outcomes and distinct biological features in multiple myeloma
Authors: Ioannis V. Kostopoulos, Ioannis Ntanasis‐Stathopoulos, Pantelis Rousakis, Panagiotis Malandrakis, Chrysanthi Panteli, Evangelos Eleutherakis‐Papaiakovou, Nikolaos Angelis, Vasiliki Spiliopoulou, Rodanthi‐Eleni Syrigou, Panagiotis Bakouros, Georgia Dimitrakopoulou, Despina Fotiou, Magdalini Migkou, Nikolaos Kanellias, Nikolaos Paschalidis, Maria Gavriatopoulou, Efstathios Kastritis, Meletios‐Athanasios Dimopoulos, Ourania E. Tsitsilonis, Evangelos Terpos
Journal: American Journal of Hematology (2024)

Abstract There is growing interest in multiple myeloma (MM) circulating tumor cells (CTCs), but their rareness in peripheral blood (PB) and inconsistency in cutoffs question their clinical utility. Herein, we applied next‐generation flow cytometry in 550 bone marrow (BM) and matched PB samples to define an optimal CTC cutoff for both transplant‐eligible and transplant‐ineligible newly diagnosed MM (NDMM) patients. Deep phenotyping was performed to investigate unique microenvironmental features associated with CTC dissemination. CTCs were detected in 90% of patients (median 0.01%; range: 0.0002%–12.6%) and increased levels associated with adverse features. Correlations were observed between high CTC percentages and a diffused MRI pattern, a distinct BM composition characterized by altered B‐cell differentiation together with an expansion of effector cells and tumor‐associated macrophages, as well as a greater phenotypic dissimilarity between BM and PB clonal cells. Progression‐free survival (PFS) and overall survival (OS) gradually worsened with each logarithmic increment of CTCs. Conversely, NDMM patients without CTCs showed unprecedented outcomes, with 5‐year PFS and OS rates of 83% and 97%, respectively. A cutoff of 0.02% CTCs was independent of the ISS, LDH, and cytogenetics in a multivariate analysis of risk factors for PFS. The 0.02% CTC cutoff synergized with the MGUS‐like phenotype and the R‐ISS for improving the risk stratification systems. MRD negativity was less frequent if CTCs were ≥0.02% at diagnosis, but whenever achieved, the poor prognosis of these patients was abrogated. This study shows the clinical utility of CTC assessment in MM and provides evidence toward a consensus cutoff for risk stratification.
Serine Depletion Promotes Anti-Tumor Immunity by Activating Mitochondrial DNA-mediated cGAS-STING Signaling
Authors: Suchandrima Saha, Monisankar Ghosh, Jinyu Li, Asher Wen, Lorenzo Galluzzi, Luis A. Martinez, David C. Montrose
Journal: Cancer Research (2024)

Abstract Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T-cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in colorectal cancer cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of antitumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors. Significance: Depriving cancer cells of serine provokes mitochondrial perturbations that induce cytosolic mitochondrial DNA accumulation and subsequent activation of cGAS-STING signaling, stimulating tumor-targeting immune responses that can be enhanced with PD-1 targeted therapy. See related commentary by Borges and Garg, p. 2569
HTS384 NCI60: The Next Phase of the NCI60 Screen
Authors: Mark W. Kunkel, Nathan P. Coussens, Joel Morris, Ronald C. Taylor, Thomas S. Dexheimer, Eric M. Jones, James H. Doroshow, Beverly A. Teicher
Journal: Cancer Research (2024)

Abstract The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for more than 30 years. The screen operated with 96-well plates, a 2-day exposure period to test agents, and following cell fixation, a visible absorbance endpoint by the protein-staining dye sulforhodamine B. In this study, we describe the next phase of this important cancer research tool, the HTS384 NCI60 screen. Although the cell lines remain the same, the updated screen is performed with 384-well plates, a 3-day exposure period to test agents, and a luminescent endpoint to measure cell viability based upon cellular ATP content. In this study, a library of 1,003 FDA-approved and investigational small-molecule anticancer agents was screened by the two NCI60 assays. The datasets were compared with a focus on targeted agents with at least six representatives in the library. For many agents, including inhibitors of EGFR, BRAF, MEK, ERK, and PI3K, the patterns of GI50 values were very similar between the screens with strong correlations between those patterns within the dataset from each screen. However, for some groups of targeted agents, including mTOR, BET bromodomain, and NAMPRTase inhibitors, there were limited or no correlations between the two datasets, although the patterns of GI50 values and correlations between those patterns within each dataset were apparent. Beginning in January 2024, the HTS384 NCI60 screen became the free screening service of the NCI to facilitate drug discovery by the cancer research community. Significance: The new NCI60 cell line screen HTS384 shows robust patterns of response to oncology agents and substantial overlap with the classic screen, providing an updated tool for studying therapeutic agents. See related commentary by Colombo and Corsello, p. 2397
Capturing relationships between suturing sub-skills to improve automatic suturing assessment
Authors: Zijun Cui, Runzhuo Ma, Cherine H. Yang, Anand Malpani, Timothy N. Chu, Ahmed Ghazi, John W. Davis, Brian J. Miles, Clayton Lau, Yan Liu, Andrew J. Hung
Journal: npj Digital Medicine (2024)

Abstract Suturing skill scores have demonstrated strong predictive capabilities for patient functional recovery. The suturing can be broken down into several substep components, including needle repositioning , needle entry angle , etc. Artificial intelligence (AI) systems have been explored to automate suturing skill scoring. Traditional approaches to skill assessment typically focus on evaluating individual sub-skills required for particular substeps in isolation. However, surgical procedures require the integration and coordination of multiple sub-skills to achieve successful outcomes. Significant associations among the technical sub-skill have been established by existing studies. In this paper, we propose a framework for joint skill assessment that takes into account the interconnected nature of sub-skills required in surgery. The prior known relationships among sub-skills are firstly identified. Our proposed AI system is then empowered by the prior known relationships to perform the suturing skill scoring for each sub-skill domain simultaneously. Our approach can effectively improve skill assessment performance through the prior known relationships among sub-skills. Through the proposed approach to joint skill assessment, we aspire to enhance the evaluation of surgical proficiency and ultimately improve patient outcomes in surgery.
Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression
Authors: Lingling Li, Dongxian Jiang, Hui Liu, Chunmei Guo, Qiao Zhang, Xuedong Li, Xiaojian Chen, Zheqi Chen, Jinwen Feng, Subei Tan, Wen Huang, Jie Huang, Chen Xu, Chen-Ying Liu, Wei Yu, Yingyong Hou, Chen Ding
Journal: Cancer Research (2024)

Abstract Colorectal cancer is the second most common malignant tumor worldwide. Analysis of the changes that occur during colorectal cancer progression could provide insights into the molecular mechanisms driving colorectal cancer development and identify improved treatment strategies. In this study, we performed an integrated multiomic analysis of 435 trace tumor samples from 148 patients with colorectal cancer, covering nontumor, intraepithelial neoplasia (IEN), infiltration, and advanced stage colorectal cancer phases. Proteogenomic analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidative phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, which occurred predominantly in the IEN and infiltration phases, respectively, and impacted the cell cycle. Mutations in TP53 were frequent in the advanced stage colorectal cancer phase and associated with the tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of colorectal cancer based on consensus molecular subtype and colorectal cancer intrinsic subtype classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of colorectal cancer based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided colorectal cancer. The AOM/DSS-induced colorectal cancer carcinogenesis mouse model indicated that DDX5 deletion due to chr17q loss promoted colorectal cancer development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of colorectal cancer and identifying the potential therapeutic targets. Significance: Characterization of the proteogenomic landscape of colorectal cancer during progression provides a multiomic map detailing the alterations in each stage of carcinogenesis and suggesting potential diagnostic and therapeutic approaches for patients.
Optimizing ATR Inhibition and Cisplatin Synergy in Ewing Sarcoma
Authors: Shunya Ohmura, Thomas G. P. Grünewald
Journal: Clinical Cancer Research (2024)

EWSR1::FLI1-mediated dysregulation of cellular machinery opens up potential new avenues for Ewing sarcoma treatment. A recent study demonstrates that pharmacologic ATR kinase inhibition dramatically synergizes with low-dose cisplatin through EWSR1::FLI1-dependent rewiring of transcription, DNA repair, and translation machinery, which could maximize the therapeutic window of the combinatory therapy. See related article by Jess et al., p. 3533.
Adaptation to tolerate high doses of arabinoxylan is associated with fecal levels of <i>Bifidobacterium longum</i>
Authors: Edward C. Deehan, Zhengxiao Zhang, Nguyen K. Nguyen, Maria Elisa Perez-Muñoz, Janis Cole, Alessandra Riva, David Berry, Carla M. Prado, Jens Walter
Journal: Gut Microbes (2024)

Dietary fiber supplements are a strategy to close the 'fiber gap' and induce targeted modulations of the gut microbiota. However, higher doses of fiber supplements cause gastrointestinal (GI) symptoms that differ among individuals. What determines these inter-individual differences is insufficiently understood. Here we analyzed findings from a six-week randomized controlled trial that evaluated GI symptoms to corn bran arabinoxylan (AX; n = 15) relative to non-fermentable microcrystalline cellulose (MCC; n = 16) at efficacious supplement doses of 25 g/day (females) or 35 g/day (males) in adults with excess weight. Self-reported flatulence, bloating, and stomach aches were evaluated weekly. Bacterial taxa involved in AX fermentation were identified by bioorthogonal non-canonical amino acid tagging. Associations between GI symptoms, fecal microbiota features, and diet history were systematically investigated. AX supplementation increased symptoms during the first three weeks relative to MCC (p < 0.05, Mann-Whitney tests), but subjects 'adapted' with symptoms reverting to baseline levels toward the end of treatment. Symptom adaptations were individualized and correlated with the relative abundance of Bifidobacterium longum at baseline (rs = 0.74, p = 0.002), within the bacterial community that utilized AX (rs = 0.69, p = 0.006), and AX-induced shifts in acetate (rs = 0.54, p = 0.039). Lower baseline consumption of animal-based foods and higher whole grains associated with less severity and better adaptation. These findings suggest that humans do 'adapt' to tolerate efficacious fiber doses, and this process is linked to their microbiome and dietary factors known to interact with gut microbes, providing a basis for the development of strategies for improved tolerance of dietary fibers.
Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice
Authors: Yongguo Zhang, Yinglin Xia, Jun Sun
Journal: Gut Microbes (2024)

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood–brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.
Data-Driven Phenotyping of Presymptomatic Type 1 Diabetes Using Longitudinal Autoantibody Profiles
Authors: Mohamed Ghalwash, Vibha Anand, Kenney Ng, Jessica L. Dunne, Olivia Lou, Markus Lundgren, William A. Hagopian, Marian Rewers, Anette-G. Ziegler, Riitta Veijola, Anette G. Ziegler, Ezio Bonifacio, Peter Achenbach, Christiane Winkler, Marian Rewers, Brigitte I. Frohnert, Jill Norris, Andrea Steck, Kathleen Waugh, Liping Yu, William A. Hagopian, Michael Killian, Angela Wolf, Jocelyn Meyer, Claire Crouch, Jared Radtke, Åke Lernmark, Helena Elding Larsson, Markus Lundgren, Marlena Maziarz, Lampros Spiliopoulos, Josefin Jönsson, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Mikael Knip, Vibha Anand, Mohamed Ghalwash, Kenney Ng, Zhiguo Li, B.C. Kwon, Harry Stravopolous, Eileen Koski, Ashwani Malhotra, Shelley Moore, Jianying Hu, Jessica Dunne, Bin Liu, Ying Li, Olivia Lou, Frank Martin
Journal: Diabetes Care (2024)

To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes.
Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease
Authors: Vanessa Dubois, Philippe Lefebvre, Bart Staels, Jerome Eeckhoute
Journal: Gut (2024)

Nuclear receptors (NRs) are ligand-dependent transcription factors required for liver development and function. As a consequence, NRs have emerged as attractive drug targets in a wide range of liver diseases. However, liver dysfunction and failure are linked to loss of hepatocyte identity characterised by deficient NR expression and activities. This might at least partly explain why several pharmacological NR modulators have proven insufficiently efficient to improve liver functionality in advanced stages of diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this perspective, we review the most recent advances in the hepatic NR field and discuss the contribution of multiomic approaches to our understanding of their role in the molecular organisation of an intricated transcriptional regulatory network, as well as in liver intercellular dialogues and interorgan cross-talks. We discuss the potential benefit of novel therapeutic approaches simultaneously targeting multiple NRs, which would not only reactivate the hepatic NR network and restore hepatocyte identity but also impact intercellular and interorgan interplays whose importance to control liver functions is further defined. Finally, we highlight the need of considering individual parameters such as sex and disease stage in the development of NR-based clinical strategies.
Acute Lymphoblastic Leukemia in Pregnant Ovarian Hypersensitivity Syndrome
Authors: Osamu Imataki, Makiko Uemura
Journal: Clinical Nuclear Medicine (2024)

Abstract Ovarian hyperstimulation syndrome (OHSS) is characterized by cystic enlargement of the ovaries and a fluid retention. This syndrome is sometimes caused after in vitro fertilization. We treated a 37-year-old woman with OHSS after in vitro fertilization, coincidentally complicated with acute lymphoblastic leukemia. Her clinical course of acute lymphoblastic leukemia was aggressive with the manifestation of OHSS, such as massive pleural effusion and massive ascites. The leukemic cells broadly infiltrated to the peritoneum, ovary, central spine fluid, and pleura. We speculated that this hyperpermeability of leukemic cells could be associated with the cytokine milieu caused by OHSS.
Neonatal Amino Acids and Acylcarnitines Associated With Maternal Blood Glucose Levels Throughout Pregnancy: Insights From the Beijing Birth Cohort Study
Authors: Wei Zheng, Xianxian Yuan, Jinqi Zhao, Weiling Han, Junhua Huang, Xin Yan, Lirui Zhang, Lulu Li, Shunan Wang, Yuanyuan Kong, Guanghui Li
Journal: Diabetes Care (2024)

OBJECTIVE To determine the association between maternal blood glucose patterns throughout pregnancy and neonatal amino acids and acylcarnitines. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study involving 11,457 singleton pregnant women without preexisting diabetes from the Beijing Birth Cohort Study, along with their neonates born between July 2021 and October 2022 in Beijing, China. Distinct maternal glucose trajectories were identified using a latent class model based on blood glucose levels across the three trimesters, and their association with neonatal circulating metabolites, including 11 amino acids and 33 acylcarnitines, was examined, adjusting for potential confounding factors. RESULTS Three distinct groups of maternal glucose trajectories were identified: consistent normoglycemia (n = 8,648), mid-to-late gestational hyperglycemia (n = 2,540), and early-onset hyperglycemia (n = 269). Mid-to-late gestational hyperglycemia was associated with decreased levels of amino acids (alanine, arginine, ornithine, and proline) involved in the arginine and proline metabolism and urea cycle pathway, as well as increased levels of C4DC+C5-OH and decreased level of C6DC and C10:1. Early-onset hyperglycemia was associated with elevated levels of free acylcarnitine and C4DC+C5-OH and a decreased level of C10:1, involved in the fatty acid oxidation pathway. However, these associations were primarily observed in male neonates rather than in female neonates. CONCLUSIONS Our findings revealed a significant link between maternal glucose trajectories throughout pregnancy and neonatal arginine and proline metabolism, urea cycle pathway, and fatty acid oxidation pathway. These results highlight the importance of maintaining optimal blood glucose levels throughout pregnancy to promote healthy neonatal metabolic outcomes.
Evoked Piloerection Sign/Pseudo-Darier Sign: a Clinical Clue to the Diagnosis of Cutaneous Leiomyomas
Authors: Sarah Moussa, Lydia Ouchene, Megha Udupa, Hessah BinJadeed, Rahaf Bashihab, Ivan V Litvinov, William D Foulkes, Elena Netchiporouk
Journal: Journal of the American Academy of Dermatology (2024)