tbuckley/cabot-search huggingface dataset:
Circulating cell-free DNA methylation patterns as non-invasive biomarkers to monitor colorectal cancer treatment efficacy without referencing primary site mutation profiles
Authors: Kazuya Yasui, Toshiaki Toshima, Ryo Inada, Yuzo Umeda, Shuya Yano, Hiroaki Tanioka, Akihiro Nyuya, Toshiyoshi Fujiwara, Takeshi Yamada, Yoshio Naomoto, Ajay Goel, Takeshi Nagasaka
Journal: Molecular Cancer (2024)

Abstract This study investigates methylation patterns in circulating cell-free DNA (ccfDNA) for their potential role in colorectal cancer (CRC) detection and the monitoring of treatment response. Through methylation microarrays and quantitative PCR assays, we analyzed 440 samples from The Cancer Genome Atlas (TCGA) and an additional 949 CRC samples. We detected partial or extensive methylation in over 85% of cases within three biomarkers: EFEMP1 , SFRP2 , and UNC5C . A methylation score for at least one of the six candidate regions within these genes' promoters was present in over 95% of CRC cases, suggesting a viable detection method. In evaluating ccfDNA from 97 CRC patients and 62 control subjects, a difference in methylation and recovery signatures was observed. The combined score, integrating both methylation and recovery metrics, showed high diagnostic accuracy, evidenced by an area under the ROC curve of 0.90 (95% CI = 0.86 to 0.94). While correlating with tumor burden, this score gave early insight into disease progression in a small patient cohort. Our results suggest that DNA methylation in ccfDNA could serve as a sensitive biomarker for CRC, offering a less invasive and potentially more cost-effective approach to augment existing cancer detection and monitoring modalities, possibly supporting comprehensive genetic mutation profiling.
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Journal: Kidney International (2024)

Kidney International is devoted to kidney research.It aims to inform the researcher, the clinical investigator, and the practicing nephrologist on all aspects of kidney research.These include the latest clinical studies on emerging developments in nephrology and the highest level of original research studies in clinical and basic kidney research.The journal reflects the field through critical reviews, commentaries, original articles, remarkable images, news features, guidelines, and problem-focused articles for the diagnosis and treatment of kidney patients.
Inference of Infectious Disease Transmission through a Relaxed Bottleneck Using Multiple Genomes Per Host
Authors: Jake Carson, Matt Keeling, David Wyllie, Paolo Ribeca, Xavier Didelot
Journal: Molecular Biology and Evolution (2024)

Abstract In recent times, pathogen genome sequencing has become increasingly used to investigate infectious disease outbreaks. When genomic data is sampled densely enough amongst infected individuals, it can help resolve who infected whom. However, transmission analysis cannot rely solely on a phylogeny of the genomes but must account for the within-host evolution of the pathogen, which blurs the relationship between phylogenetic and transmission trees. When only a single genome is sampled for each host, the uncertainty about who infected whom can be quite high. Consequently, transmission analysis based on multiple genomes of the same pathogen per host has a clear potential for delivering more precise results, even though it is more laborious to achieve. Here, we present a new methodology that can use any number of genomes sampled from a set of individuals to reconstruct their transmission network. Furthermore, we remove the need for the assumption of a complete transmission bottleneck. We use simulated data to show that our method becomes more accurate as more genomes per host are provided, and that it can infer key infectious disease parameters such as the size of the transmission bottleneck, within-host growth rate, basic reproduction number, and sampling fraction. We demonstrate the usefulness of our method in applications to real datasets from an outbreak of Pseudomonas aeruginosa amongst cystic fibrosis patients and a nosocomial outbreak of Klebsiella pneumoniae.
H+‐slip correlated to rotor free‐wheeling as cause of F<sub>1</sub>F<sub>O</sub>‐ATPase dysfunction in primary mitochondrial disorders
Authors: Salvatore Nesci, Giovanni Romeo
Journal: Medicinal Research Reviews (2024)

Abstract Inborn errors of metabolism are related to mitochondrial disorders caused by dysfunction of the oxidative phosphorylation (OXPHOS) system. Congenital hypermetabolism in the infant is a rare disease belonging to Luft syndrome, nonthyroidal hypermetabolism, arising from a singular example of a defect in OXPHOS. The mitochondria lose coupling of mitochondrial substrates oxidation from the ADP phosphorylation. Since Luft syndrome is due to uncoupled cell respiration responsible for deficient in ATP production that originates in the respiratory complexes, a de novo heterozygous variant in the catalytic subunit of mitochondrial F 1 F O ‐ATPase arises as the main cause of an autosomal dominant syndrome of hypermetabolism associated with dysfunction in ATP production, which does not involve the respiratory complexes. The F 1 F O ‐ATPase works as an embedded molecular machine with a rotary action using two different motor engines. The F O , which is an integral domain in the membrane, dissipates the chemical potential difference for H + , a proton motive force (Δ p ), across the inner membrane to generate a torsion. The F 1 domain—the hydrophilic portion responsible for ATP turnover—is powered by the molecular rotary action to synthesize ATP. The structural and functional coupling of F 1 and F O domains support the energy transduction for ATP synthesis. The dissipation of Δ p by means of an H + slip correlated to rotor free‐wheeling of the F 1 F O ‐ATPase has been discovered to cause enzyme dysfunction in primary mitochondrial disorders. In this insight, we try to offer commentary and analysis of the molecular mechanism in these impaired mitochondria.
Corrigendum to “A novel nanoluciferase transgenic reporter measures proteinuria in zebrafish.” Kidney Int. 2022;102:815–827
Authors: Richard W. Naylor, Emmanuel Lemarie, Anthony Jackson-Crawford, J. Bernard Davenport, Aleksandr Mironov, Martin Lowe, Rachel Lennon
Journal: Kidney International (2024)

DOI of original article: https://doi.org/10.1016/j.kint.2022.05.019 The authors regret that the wrong sequence and concentration for the nphs2 morpholino were described in the original version of the manuscript. The sequence and concentration of the nphs2 morpholino have been corrected to TGCGATTTAAAACGTGTACCAGGGC and 1.0 mM, respectively, in the "Morpholino oligonucleotide treatments" portion of the Extended Supplementary Methods, where this information is described, and have been corrected in the article online. The data obtained with the morpholino (shown in Figure 3b of the main manuscript) are unchanged. The authors would like to apologize for any inconvenience caused. Download .pdf (5.01 MB) Help with pdf files Supplementary File (PDF) Figure S1. Comparison of luminescence in wild-type (WT) versus NLD3 adult tissue. Figure S2. Histology of adult liver in wild-type and NL-D3 transgenic zebrafish. Figure S3. Dextran uptake classification. Figure S4. NL-D3 proteinuria can be observed after a short incubation time. Figure S5. Standard curve data. Figure S6. Tracking of indels by decomposition (TIDE) analysis shows mutagenesis at gRNA site 1 in the Alport zebrafish crispants. Figure S7. Single allele analysis of col4a3 and col4a4 crispants. Figure S8. Nonannotated transmission electron microscopy (TEM) images of glomeruli in control and col4a3 and col4a4 crispants. Figure S9. Increasing 2,3-butanedione 2-monoxime (2,3-BDM) dose results in increasing effect on heart rate in zebrafish embryos. Extended Supplementary Methods. A novel nanoluciferase transgenic reporter measures proteinuria in zebrafishKidney InternationalVol. 102Issue 4PreviewThe zebrafish is an important animal system for modeling human diseases. This includes kidney dysfunction as the embryonic kidney (pronephros) shares considerable molecular and morphological homology with the human nephron. A key clinical indicator of kidney disease is proteinuria, but a high-throughput readout of proteinuria in the zebrafish is currently lacking. To remedy this, we used the Tol2 transposon system to generate a transgenic zebrafish line that uses the fabp10a liver-specific promoter to over-express a nanoluciferase molecule fused with the D3 domain of Receptor-Associated Protein (a type of molecular chaperone) which we term NL-D3. Full-Text PDF Open Access
Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis
Authors: Brad H. Rovin, Isabelle M. Ayoub, Tak Mao Chan, Zhi-Hong Liu, Juan M. Mejía-Vilet, Ethan M. Balk, Craig E. Gordon, Gaelen Adam, Marcello A. Tonelli, Michael Cheung, Amy Earley, Jürgen Floege
Journal: Kidney International (2024)

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases was published in 2021. Since then, the pace of drug development for glomerular diseases has accelerated, due in large part to rapidly accumulating insights into disease pathogenesis from genetic and molecular studies of afflicted patients. To keep the Glomerular Diseases Guideline as current as possible, KDIGO made a commitment to the nephrology community to provide periodic updates, based on new developments for each disease. After the 2021 guideline was published, two novel drugs received regulatory approval for the management of lupus nephritis, leading to the first KDIGO guideline update. Herein, an executive summary of the most important guideline changes from the Lupus Nephritis chapter is provided as a quick reference.
Multi-omic approaches for host-microbiome data integration
Authors: Ashwin Chetty, Ran Blekhman
Journal: Gut Microbes (2024)

The gut microbiome interacts with the host through complex networks that affect physiology and health outcomes. It is becoming clear that these interactions can be measured across many different omics layers, including the genome, transcriptome, epigenome, metabolome, and proteome, among others. Multi-omic studies of the microbiome can provide insight into the mechanisms underlying host-microbe interactions. As more omics layers are considered, increasingly sophisticated statistical methods are required to integrate them. In this review, we provide an overview of approaches currently used to characterize multi-omic interactions between host and microbiome data. While a large number of studies have generated a deeper understanding of host-microbiome interactions, there is still a need for standardization across approaches. Furthermore, microbiome studies would also benefit from the collection and curation of large, publicly available multi-omics datasets.
Kidney allograft venous obstruction from polycystic kidney disease
Authors: David Massicotte-Azarniouch, Pierre-Antoine Brown, Jana Pichovsky, Jeffrey E. Warren
Journal: Kidney International (2024)

A 63-year-old woman, a kidney transplant recipient of a deceased donor kidney from 5 years prior, was seen in routine follow-up in the transplant clinic with progressively worsening graft function, along with bilateral leg edema and abdominal discomfort over a few weeks to months onset. Her native kidney disease was polycystic kidney disease. Maintenance immunosuppression consisted of tacrolimus, mycophenolate, and prednisone. Her post-transplant course had been remarkable for ureteric obstruction due to ischemic stenosis and calcification at 3 months post-transplant, which had required ureteric reconstruction and reimplantation. She also had cytomegalovirus viremia 9 months post-transplant (cytomegalovirus mismatch donation), which resolved with valganciclovir treatment. The rest of her course had been unremarkable, and her baseline creatine level was between 100 and 110 μmol/L. On presentation, her creatinine level was 136 μmol/L, and this progressively increased to 197 μmol/L over about a month. A contrasted computed tomography scan of the abdomen and pelvis was done for her abdominal discomfort and to rule out hydronephrosis. This revealed venous obstruction of the inferior vena cava (Figure 1) and venous outflow obstruction of the allograft due to a markedly enlarged native right polycystic kidney (Figure 2). She was admitted to the hospital, where she underwent urgent native right nephrectomy. The kidney measured 22 × 14 × 10 cm (Supplementary Figure S1). After nephrectomy, leg edema rapidly resolved and serum creatinine level markedly improved to 136 μmol/L on postoperative day 3 and then to 115 μmol/L on follow-up in the clinic at 1-week postnephrectomy. Leg edema had completely resolved. Venous obstruction from enlarged polycystic kidneys has been described in the nontransplant population; however, obstruction compromising venous outflow from a kidney allograft is an extremely rare occurrence. This case is a reminder to always consider the patient's native disease when faced with worsening kidney allograft function, even when the native disease is polycystic kidney disease, which is not typically thought to cause direct allograft injury.Figure 2Venous obstruction of kidney allograft. Three-dimensional reconstruction of coronal computed tomography shows congested renal vein of the transplant kidney (yellow arrow), secondary to venous outflow obstruction due to severe inferior vena cava compression.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient provided verbal consent for this report. Download .docx (.47 MB) Help with docx files Supplementary File (Word) Figure S1. Postnephrectomy, macroscopic view of enlarged polycystic kidney.
ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban
Authors: An-Jing Ren, Chunchun Wei, Ya-Jin Liu, Mengna Liu, Ping Wang, Juan Fan, Kai Wang, Sha Zhang, Zhenbang Qin, Qiu-Xiao Ren, Yanjun Zheng, Yu-Xia Chen, Zhifang Xie, Ling Gao, Yi Zhu, Youyi Zhang, Huang-Tian Yang, Weiping J. Zhang
Journal: Circulation Research (2024)

Intracellular Ca
Current challenges and future of agricultural genomes to phenomes in the USA
Authors: Christopher K. Tuggle, Jennifer L. Clarke, Brenda M. Murdoch, Eric Lyons, Nicole M. Scott, Bedrich Beneš, Jacqueline D. Campbell, Henri Chung, Courtney L. Daigle, Sruti Das Choudhury, Jack C. M. Dekkers, Joao R. R. Dórea, David S. Ertl, Max Feldman, Breno O. Fragomeni, Janet E. Fulton, Carmela R. Guadagno, Darren E. Hagen, Andrew S. Hess, Luke M. Kramer, Carolyn J. Lawrence-Dill, Alexander E. Lipka, Thomas Lübberstedt, Fiona M. McCarthy, Stephanie D. McKay, Seth C. Murray, Penny K. Riggs, Troy N. Rowan, Moira J. Sheehan, Juan P. Steibel, Addie M. Thompson, Kara J. Thornton, Curtis P. Van Tassell, Patrick S. Schnable
Journal: Genome biology (2024)

Abstract Dramatic improvements in measuring genetic variation across agriculturally relevant populations (genomics) must be matched by improvements in identifying and measuring relevant trait variation in such populations across many environments (phenomics). Identifying the most critical opportunities and challenges in genome to phenome (G2P) research is the focus of this paper. Previously (Genome Biol, 23(1):1–11, 2022), we laid out how Agricultural Genome to Phenome Initiative (AG2PI) will coordinate activities with USA federal government agencies expand public–private partnerships, and engage with external stakeholders to achieve a shared vision of future the AG2PI. Acting on this latter step, AG2PI organized the “Thinking Big: Visualizing the Future of AG2PI” two-day workshop held September 9–10, 2022, in Ames, Iowa, co-hosted with the United State Department of Agriculture’s National Institute of Food and Agriculture (USDA NIFA). During the meeting, attendees were asked to use their experience and curiosity to review the current status of agricultural genome to phenome (AG2P) work and envision the future of the AG2P field. The topic summaries composing this paper are distilled from two 1.5-h small group discussions. Challenges and solutions identified across multiple topics at the workshop were explored. We end our discussion with a vision for the future of agricultural progress, identifying two areas of innovation needed: (1) innovate in genetic improvement methods development and evaluation and (2) innovate in agricultural research processes to solve societal problems. To address these needs, we then provide six specific goals that we recommend be implemented immediately in support of advancing AG2P research.
SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis
Authors: Ruizhe Ren, Sha Ding, Kefan Ma, Yuanqing Jiang, Yiran Wang, Junbo Chen, Yunyun Wang, Yaohui Kou, Xiao Fan, Xiaolong Zhu, Lingfeng Qin, Cong Qiu, Michael Simons, Xiyang Wei, Luyang Yu
Journal: Circulation Research (2024)

BACKGROUND: Angiogenesis, which plays a critical role in embryonic development and tissue repair, is controlled by a set of angiogenic signaling pathways. As a TF (transcription factor) belonging to the basic helix-loop-helix family, HEY (hairy/enhancer of split related with YRPW motif)-1 (YRPW motif, abbreviation of 4 highly conserved amino acids in the motif) has been identified as a key player in developmental angiogenesis. However, the precise mechanisms underlying HEY1’s actions in angiogenesis remain largely unknown. Our previous studies have suggested a potential role for posttranslational SUMOylation in the dynamic regulation of vascular development and organization. METHODS: Immunoprecipitation, mass spectrometry, and bioinformatics analysis were used to determine the biochemical characteristics of HEY1 SUMOylation. The promoter-binding capability of HEY1 was determined by chromatin immunoprecipitation, dual luciferase, and electrophoretic mobility shift assays. The dimerization pattern of HEY1 was determined by coimmunoprecipitation. The angiogenic capabilities of endothelial cells were assessed by CCK-8 (cell counting kit-8), 5-ethynyl-2-deoxyuridine staining, wound healing, transwell, and sprouting assays. Embryonic and postnatal vascular growth in mouse tissues, matrigel plug assay, cutaneous wound healing model, oxygen-induced retinopathy model, and tumor angiogenesis model were used to investigate the angiogenesis in vivo. RESULTS: We identified intrinsic endothelial HEY1 SUMOylation at conserved lysines by TRIM28 (tripartite motif containing 28) as the unique E3 ligase. Functionally, SUMOylation facilitated HEY1-mediated suppression of angiogenic RTK (receptor tyrosine kinase) signaling and angiogenesis in primary human endothelial cells and mice with endothelial cell–specific expression of wild-type HEY1 or a SUMOylation-deficient HEY1 mutant. Mechanistically, SUMOylation facilitates HEY1 homodimer formation, which in turn preserves HEY1’s DNA-binding capability via recognition of E-box promoter elements. Therefore, SUMOylation maintains HEY1’s function as a repressive TF controlling numerous angiogenic genes, including RTKs and Notch pathway components. Proangiogenic stimuli induce HEY1 deSUMOylation, leading to heterodimerization of HEY1 with HES (hairy and enhancer of split)-1, which results in ineffective DNA binding and loss of HEY1’s angiogenesis-suppressive activity. CONCLUSIONS: Our findings demonstrate that reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine-tuning the transcriptional activity of HEY1. Specifically, SUMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA-binding capability in endothelial cells.
2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
Authors: Theresa A. McDonagh, Marco Metra, Marianna Adamo, Roy S. Gardner, Andreas Baumbach, Michael Böhm, Haran Burri, Javed Butler, Jelena Čelutkienė, Ovidiu Chioncel, John G.F. Cleland, Maria Generosa Crespo‐Leiro, Dimitrios Farmakis, Martine Gilard, Stephane Heymans, Arno W. Hoes, Tiny Jaarsma, Ewa A. Jankowska, Mitja Lainscak, Carolyn S.P. Lam, Alexander R. Lyon, John J.V. McMurray, Alexandre Mebazaa, Richard Mindham, Claudio Muneretto, Massimo Francesco Piepoli, Susanna Price, Giuseppe M.C. Rosano, Frank Ruschitzka, Anne Kathrine Skibelund
Journal: European Journal of Heart Failure (2024)
Tumor-Associated Macrophages in Merkel Cell Carcinoma: Old Balances, New Checks
Authors: Ann W. Silk, Diwakar Davar
Journal: Clinical Cancer Research (2024)

A recent report sheds light on the tumor-associated macrophages (TAM) in Merkel cell carcinoma (MCC), and the association of S100A8-expressing TAMs with resistance to anti-PD-(L)1 inhibitors. These data improve our understanding about why some tumors with brisk tumor-infiltrating lymphocytes do not respond to immunotherapy and provide a compelling rationale to target myeloid checkpoints in MCC. See related article by Tabachnick-Cherny et al., p. xxxx.
Levetiracetam: A Potent Sword against Microglia Polarization in Gliomas
Authors: Xiaoteng Cui, Qixue Wang, Xiaomin Liu, Chunsheng Kang
Journal: Clinical Cancer Research (2024)

Summary Crosstalk between tumor cells and peritumoral cells contributes to immunosuppressive microenvironment formation in glioblastomas (GBM). A recent study revealed that glioma stem cells activated neuronal activity to promote microglial M2 polarization, leading to GBM progression, which could be pharmacologically blocked by levetiracetam, providing a practical strategy for GBM immunotherapy. See related article by Guo et al., p. 1160
Inpatient Costs of Treating Patients With COVID-19
Authors: Kandice A. Kapinos, Richard M. Peters, Robert E. Murphy, Samuel F. Hohmann, Ankita Podichetty, Raymond S. Greenberg
Journal: JAMA Network Open (2024)

Importance With more than 6.2 million hospitalizations due to COVID-19 in the US, recognition of the average hospital costs to provide inpatient care during the pandemic is necessary to understanding the national medical resource use and improving public health readiness and related policies. Objective To examine the mean cost to provide inpatient care to treat COVID-19 and how it varied through the pandemic waves and by important sociodemographic patient characteristics. Design, Setting, and Participants This cross-sectional study used inpatient-level data from March 1, 2020, to March 31, 2022, extracted from a repository of clinical, administrative, and financial information covering 97% of academic medical centers across the US. Main Outcomes and Measures Cost to produce care for each stay was calculated using direct hospital costs to provide care adjusted for geographic differences in labor costs using area wage indices. Results The sample included 1 333 404 stays with a primary or secondary COVID-19 diagnosis from 841 hospitals. The cohort included 692 550 (52%) men, with mean (SD) age of 59.2 (17.5) years. The adjusted mean cost of an inpatient stay was $11 275 (95% CI, $11 252-$11 297) overall, increasing from $10 394 (95% CI, $10 228-$10 559) at the end of March 2020 to $13 072 (95% CI, $12 528-$13 617) by the end of March 2022. Patients with specific comorbidities had significantly higher mean costs than their counterparts: those with obesity incurred an additional $2924 in inpatient stay costs, and those with coagulation deficiency incurred an additional $3017 in inpatient stay costs. Stays during which the patient required extracorporeal membrane oxygenation (ECMO) had an adjusted mean cost of $36 484 (95% CI, $34 685-$38 284). Conclusions and Relevance In this cross-sectional study, an adjusted mean hospital cost to provide care for patients with COVID-19 increased more than 5 times the rate of medical inflation overall. This appeared to be explained partly by changes in the use of ECMO, which increased over time.