tbuckley/cabot-search huggingface dataset:
Graphasing: phasing diploid genome assembly graphs with single-cell strand sequencing
Authors: Mir Henglin, Maryam Ghareghani, William T. Harvey, David Porubsky, Sergey Koren, Evan E. Eichler, Peter Ebert, Tobias Marschall
Journal: Genome biology (2024)

Abstract Haplotype information is crucial for biomedical and population genetics research. However, current strategies to produce de novo haplotype-resolved assemblies often require either difficult-to-acquire parental data or an intermediate haplotype-collapsed assembly. Here, we present Graphasing, a workflow which synthesizes the global phase signal of Strand-seq with assembly graph topology to produce chromosome-scale de novo haplotypes for diploid genomes. Graphasing readily integrates with any assembly workflow that both outputs an assembly graph and has a haplotype assembly mode. Graphasing performs comparably to trio phasing in contiguity, phasing accuracy, and assembly quality, outperforms Hi-C in phasing accuracy, and generates human assemblies with over 18 chromosome-spanning haplotypes.
The Risk and Reversibility of Osimertinib-related Cardiotoxicity in a Real-World Population
Authors: Minjung Bak, Hyukjin Park, Se-Hoon Lee, Nuri Lee, Myung-Ju Ahn, Jin Seok Ahn, Hyun Ae Jung, Sehhoon Park, Jinhyun Cho, Jihoon Kim, Sung-Ji Park, Sung-A Chang, Sang-Chol Lee, Seung Woo Park, Eun Kyoung Kim
Journal: Journal of Thoracic Oncology (2024)
How Biologics Have Changed the Drug Discovery Landscape
Authors: Paul McGonigle
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.
Risk factors for locoregional relapse after segmentectomy: Supplementary analysis of the JCOG0802/WJOG4607L trial
Authors: Kazuo Nakagawa, Shun-Ichi Watanabe, Masashi Wakabayashi, Masaya Yotsukura, Takahiro Mimae, Aritoshi Hattori, Tomohiro Miyoshi, Mitsuhiro Isaka, Makoto Endo, Hiroshige Yoshioka, Yasuhiro Tsutani, Tetsuya Isaka, Tomohiro Maniwa, Ryu Nakajima, Kenji Suzuki, Keiju Aokage, Hisashi Saji, Masahiro Tsuboi, Morihito Okada, Hisao Asamura, Yuta Sekino, Kenichi Nakamura, Haruhiko Fukuda
Journal: Journal of Thoracic Oncology (2024)
An international, multi-center study evaluated rituximab therapy in childhood steroid-resistant nephrotic syndrome.
Authors: Eugene Yu-hin Chan, Aditi Sinha, Ellen L.M. Yu, Naureen Akhtar, Andrea Angeletti, Arvind Bagga, Sushmita Banerjee, Olivia Boyer, Chang-Yien Chan, Anna Francis, Gian Marco Ghiggeri, Riku Hamada, Pankaj Hari, Nakysa Hooman, Luke Sydney Hopf, Mohamad Ikram I, Iftikhar Ijaz, Dmytro D. Ivanov, Suprita Kalra, Hee Gyung Kang, Laura Lucchetti, Francesca Lugani, Alison Lap-tak Ma, William Morello, María Dolores Camargo Muñiz, Subal Kumar Pradhan, Larisa Prikhodina, Reem H. Raafat, Rajiv Sinha, Sharon Teo, Kouki Tomari, Marina Vivarelli, Hazel Webb, Hui Kim Yap, Desmond Yat-hin Yap, Kjell Tullus
Journal: Kidney International (2024)

The efficacy and safety of rituximab in childhood steroid-resistant nephrotic syndrome (SRNS) remains unclear. Therefore, we conducted a retrospective cohort study at 28 pediatric nephrology centers from 19 countries in Asia, Europe, North America and Oceania to evaluate this. Children with SRNS treated with rituximab were analyzed according to the duration of calcineurin inhibitors (CNIs) treatment before rituximab [6 months or more (CNI-resistant) and under 6 months]. Primary outcome was complete/partial remission (CR/PR) as defined by IPNA/KDIGO guidelines. Secondary outcomes included kidney failure and adverse events. Two-hundred-forty-six children (mean age, 6.9 years; 136 boys; 57% focal segmental glomerulosclerosis, FSGS) were followed a median of 32.4 months after rituximab. All patients were in non-remission before rituximab. (146 and 100 children received CNIs for 6 month or more or under 6 months before rituximab, respectively). In patients with CNI-resistant SRNS, the remission rates (CR/PR) at 3-, 6-, 12- and 24-months were 26% (95% confidence interval 19.3-34.1), 35.6% (28.0-44.0), 35.1% (27.2-43.8) and 39.1% (29.2-49.9), respectively. Twenty-five patients were in PR at 12-months, of which 22 had over 50% reduction in proteinuria from baseline. The remission rates among children treated with CNIs under 6 months before rituximab were 42% (32.3-52.3), 52% (41.8-62.0), 54% (44.3-64.5) and 60% (47.6-71.3) at 3-, 6-, 12-, and 24-months. Upon Kaplan-Meier analysis, non-remission and PR at 12-months after rituximab, compared to CR, were associated with significantly worse kidney survival Adverse events occurred in 30.5% and most were mild. Thus, rituximab enhances remission in a subset of children with SRNS, is generally safe and CR following rituximab is associated with favorable kidney outcome.Graphical abstract
Drought-responsive dynamics of H3K9ac-marked 3D chromatin interactions are integrated by OsbZIP23-associated super-enhancer-like promoter regions in rice
Authors: Yu Chang, Jiahan Liu, Minrong Guo, Weizhi Ouyang, Jiapei Yan, Lizhong Xiong, Xingwang Li
Journal: Genome biology (2024)

In response to drought stress (DS), plants undergo complex processes that entail significant transcriptome reprogramming. However, the intricate relationship between the dynamic alterations in the three-dimensional (3D) genome and the modulation of gene co-expression in drought responses remains a relatively unexplored area.
Clinical significance of a prospective large genomic screening for small-cell lung cancer: the genetic classification and a biomarker driven phase II trial of gedatolisib
Authors: Shigeki Umemura, Hibiki Udagawa, Takaya Ikeda, Haruyasu Murakami, Haruko Daga, Ryo Toyozawa, Toshiyuki Kozuki, Jun Sakakibara-Konishi, Yuichiro Ohe, Masahiro Morise, Terufumi Kato, Masato Shingyoji, Satoshi Hara, Naoki Furuya, Shuhei Teranishi, Saori Takata, Shingo Miyamoto, Ichiro Nakachi, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Genichiro Ishii, Katsuya Tsuchihara, Eri Sugiyama, Keisuke Kirita, Tetsuya Sakai, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Koichi Goto
Journal: Journal of Thoracic Oncology (2024)
Genetic alteration of class I HLA in cutaneous T-cell lymphoma
Authors: Alexa C Kwang, George E Duran, Sebastian Fernandez-Pol, Safa Najidh, Shufeng Li, Armando N Bastidas Torres, Erica B Wang, Melba Herrera, Tarek I Bandali, David M Kurtz, Youn H Kim, Michael S Khodadoust
Journal: Blood (2024)

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci revealed at least one HLA abnormality in 26/65 patients (40%). Twelve unique somatic HLA mutations were identified across nine patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with decreased total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presentation of greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient receiving pembrolizumab, where resistance to pembrolizumab was associated with elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.
A clinical-genetic (CG) circulating tumor DNA (ctDNA)-based prognostic model for predicting overall survival (OS) in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with potent androgen receptor inhibition (Alliance).
Authors: Susan Halabi, Bin Luo, Siyuan S Guo, Todd Knutson, Jacqueline Lyman, Anna Kobilka, Himisha Beltran, Emmanuel S. Antonarakis, Jonathan E. Rosenberg, Matt D. Galsky, Charles J. Ryan, William Kevin Kelly, Eric J. Small, Michael J. Morris, Scott M. Dehm, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2024)

5007 Background: We have previously developed and validated a clinical prognostic model of OS in mCRPC men that included these variables: performance status, disease site, opioid analgesic use, lactate dehydrogenase, albumin, hemoglobin, prostate specific antigen, and alkaline phosphatase. The goal of this analysis is to improve upon the clinical model of OS by incorporating ctDNA pathogenic genetic alterations (PGAs). Methods: Data from the A031201 phase 3 trial of enzalutamide+/- abiraterone were used to develop and validate the CG model of OS. Cell-free DNA was isolated from plasma and analyzed using a 69-gene targeted DNA-sequencing assay for detection of ctDNA PGAs. Genetic features were identified based on feature importance using a random survival forest and the final CG model was trained including clinical and selected genetic factors. Model discrimination was assessed using time-dependent area under the receiver operating characteristic curve (tAUC). Results: Data were available on 776 patients. In addition to clinical variables, the model included in this order: gains in AR and the AR enhancer, MYC , RSPO2 , and losses and/or PGAs of ZBTB16 , PTEN , MSH6 , PPP2R2A , NKX3-1 , TP53 , FANCA , RB1 , APC , CHD1 , and BRCA2 , and ichorCNA tumor fraction. tAUCs in clinical and CG models were 0.72 (95% CI=0.72-0.73) and 0.77 (95% CI= 0.76-0.77). Median OS and the hazard ratios by the three- and four- prognostic risk groups are presented in the table. Conclusions: CG model identified novel ctDNA PGAs prognostic of OS and can be utilized to classify patients into risk groups useful in selecting patients in future trials of mCRPC. Clinical trial information: NCT01949337 . Median OS and hazard ratios by the three- and four-prognostic risk groups. Prognostic Risk Groups* Median Overall Survival (95% Confidence Interval (CI)), months Hazard Ratio (95% CI) 3-Prognostic Risk Groups LowIntermediatePoor 58.9 (50.1- NR)35.5 (32.3- 40.2)19.3 (17.3- 21.5) 0.22 (0.17- 0.27)0.42 (0.35- 0.51)Reference 4-Prognostic Risk GroupsLowLow IntermediateIntermediate PoorPoor 64.2 (52.8- NR)43.6 (38.2- 48.9)31.1 (28.3- 33.6)17.0 (16.0- 18.9) 0.15 (0.11- 0.19)0.26 (0.20- 0.33)0.43 (0.34- 0.53)Reference *Patients classified into prognostic risk groups based on the tertile or the quartile of the predicted risk.
18F-FDG PET/CT Finding of Bilateral Breast Relapse in a Male Acute Lymphoblastic Leukemia Patient
Authors: Xilan Yao, Hongrong Wang, Jigang Yang
Journal: Clinical Nuclear Medicine (2024)

Abstract Extramedullary relapse with involvement of the breasts by acute lymphoblastic leukemia is rare. Herein, we report a case of bilateral breast relapse of acute B-cell lymphoblastic leukemia in a man detected by 18 F-FDG PET/CT. After systematic therapy, follow-up PET/CT showed a complete response of the bilateral breasts and the axillary lymph nodes.
Erratum: Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O6-Methylguanine–DNA Methyltransferase Biomarker Analyses
Journal: Journal of Clinical Oncology (2024)
Association Between Baseline Driving Pressure and Mortality in Very Old Patients with ARDS
Authors: Eleni Papoutsi, Konstantinos Gkirgkiris, Vasiliki Tsolaki, Ioannis Andrianopoulos, Konstantinos Pontikis, Katerina Vaporidi, Spyridon Gkoufas, Magdalini Kyriakopoulou, Anna Kyriakoudi, Elisabeth Paramythiotou, Evangelos Kaimakamis, Clementine Bostantzoglou, Militsa Bitzani, Mary Daganou, Vasilios Koulouras, Eumorfia Kondili, Antonia Koutsoukou, Ioanna Dimopoulou, Anastasia Kotanidou, Ilias I. Siempos
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Due to effects of aging on the respiratory system, it is conceivable that the association between driving pressure and mortality depends on age. Objective: We endeavored to evaluate whether the association between driving pressure and mortality of patients with acute respiratory distress syndrome (ARDS) varies across the adult lifespan, hypothesizing that it is stronger in older, including very old (≥80 years), patients. Methods: We performed a secondary analysis of individual patient-level data from seven ARDS Network and PETAL Network randomized controlled trials ("ARDSNet cohort"). We tested our hypothesis in a second, independent, national cohort ("Hellenic cohort"). We performed both binary logistic and Cox regression analyses including the interaction term between age (as a continuous variable) and driving pressure at baseline (i.e., the day of trial enrollment) as the predictor, and 90-day mortality as the dependent variable. Findings: Based on data from 4567 patients with ARDS included in the ARDSNet cohort, we found that the effect of driving pressure on mortality depended on age (p=0.01 for the interaction between age as a continuous variable and driving pressure). The difference in driving pressure between survivors and non-survivors significantly changed across the adult lifespan (p<0.01). In both cohorts, a driving pressure threshold of 11 cmH2O was associated with mortality in very old patients. Interpretation: Data from randomized controlled trials with strict inclusion criteria suggest that the effect of driving pressure on mortality of patients with ARDS may depend on age. These results may advocate for a personalized age-dependent mechanical ventilation approach.
Microbiota-derived acetate is associated with functionally optimal virus-specific CD8 <sup>+</sup> T cell responses to influenza virus infection via GPR43-dependent metabolic reprogramming
Authors: Jingjing Qiu, Chunwei Shi, Yanan Zhang, Tianming Niu, Shuxian Chen, Guilian Yang, Shu Jeffrey Zhu, Chunfeng Wang
Journal: Gut Microbes (2024)

The microbiota-associated factors that affect host susceptibility and adaptive immunity to influenza A virus (IAV) infection have not been fully elucidated. By comparing the microbiota composition between survivors and mice that succumbed to IAV strain PR8 infection, we identified that the commensal bacterium
Accelerating Oral Wound Healing Using Bilayer Biomaterial Delivery of FTY720 Immunotherapy
Authors: Afra I. Toma, Daniel Shah, Daniela Roth, Jeremie Oliver Piña, Lauren Hymel, Thomas Turner, Archana Kamalakar, Ken Liu, Perry Bartsch, Leon Jacobs, Rena D'Souza, Dennis Liotta, Edward Botchwey, Nick J. Willett, Steven L. Goudy
Journal: Advanced Healthcare Materials (2024)

Orofacial clefts are the most common congenital craniofacial anomaly. Adverse healing following cleft palate repair can lead to oronasal fistula (ONF), a persistent connection between the oral and nasal cavities. Although human allograft tissues are currently the gold standard for ONF repair, these methods carry risks of infection and rejection, often requiring surgical revision. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. An FDA-approved immunomodulatory drug, FTY720, is repurposed to reduce lymphocyte egress and induce immune cell fate switching toward pro-regenerative phenotypes. In this study, a bilayer biomaterial system is engineered using Tegaderm to secure and control the delivery of FTY720-nanofiber scaffolds (FTY720-NF). The release kinetics of the bilayer FTY720-NF is optimized to maintain drug release for up to 7 days, ensuring safe transdermal absorption and tissue biodistribution. The comprehensive immunophenotyping results demonstrate a regenerative state transition in hybrid immune cells recruited to the wound site. Further, histological evaluations reveal a significant ONF closure in mice by day 7 following bilayer FTY720-NF implantation. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options in pediatric patients.
Collaborative Enhancement of Diabetic Wound Healing and Skin Regeneration by Recombinant Human Collagen Hydrogel and hADSCs
Authors: Weishi Kong, Yulu Bao, Wei Li, Dingding Guan, Yating Yin, Yongqiang Xiao, Shihui Zhu, Yu Sun, Zhaofan Xia
Journal: Advanced Healthcare Materials (2024)

Stem cell-based therapies hold significant promise for chronic wound healing and skin appendages regeneration, but challenges such as limited stem cell lifespan and poor biocompatibility of delivery systems hinder clinical application. In this study, an in situ delivery system for human adipose-derived stem cells is developed (hADSCs) to enhance diabetic wound healing. The system utilizes a photo-crosslinking recombinant human type III collagen (rHCIII) hydrogel to encapsulate hADSCs, termed the hADSCs@rHCIII hydrogel. This hydrogel undergoes local crosslinking at the wound site, establishing a sturdy 3D niche suitable for stem cell function. Consequently, the encapsulated hADSCs exhibit strong attachment and spreading within the hydrogels, maintaining their proliferation, metabolic activity, and viability for up to three weeks in vitro. Importantly, in vivo studies demonstrate that the hADSCs@rHCIII hydrogel achieves significant in situ delivery of stem cells, prolonging their retention within the wound. This ultimately enhances their immunomodulatory capabilities, promotes neovascularization and granulation tissue formation, facilitates matrix remodeling, and accelerates healing in a diabetic mouse wound model. Collectively, these findings highlight the potential of the conveniently-prepared and user-friendly hADSCs@rHCIII hydrogel as a promising therapeutic approach for diabetic wound treatment and in situ skin regeneration.
Supramolecular Porphyrin Photosensitizers Based on Host−Guest Recognition for In Situ Bacteria‐Responsive Near‐Infrared Photothermal Therapy
Authors: Dan Wu, Xianlong Du, Qiangqiang Xue, Jie Zhou, Kunmin Ping, Yibin Cao, Shuang Liu, Qing Zhu
Journal: Advanced Healthcare Materials (2024)

Antibiotic resistance resulting from the overuse of antibiotics sets a high challenge for brutal antimicrobial treatment. Although photothermal therapy (PTT) overcomes the awkward situation of antibiotic resistance, it usually mistakenly kills the beneficial bacteria strains when eliminating pernicious bacteria. Specifically recognizing and damaging the target pathogens is urgently required for PTT-mediated sterilization strategy. Based on the host-guest recognition between cucurbit[10]uril (CB[10]) and porphyrins, two water-soluble supramolecular porphyrins are designed and implement selective bactericidal effect via in situ bacteria-responsive near-infrared (NIR) PTT. With the help of CB[10], the π-π stacking and hydrophobic interactions of porphyrins are efficiently inhibited, thus contributing to a good photostability and a high photothermal conversion efficiency. Attributing to the matching reduction potential between facultative anaerobic Escherichia coli (E. coli) and porphyrins, they are selectively in situ reduced into supramolecular phlorin and supramolecular chlorin by E. coli, successfully achieving a selective sterilization against E. coli. In vivo, the in situ bacteria-responsive NIR PTT systems also promote the quick recovery of E. coli-infected abscesses and trauma on mice without inducing obvious systemic toxicity, providing a new alternative to the current antibiotics and helping relieve the global public health crisis of abusive antibiotics.
Iron‐MOFs for Biomedical Applications
Authors: Zhihao Yu, Mathilde Lepoitevin, Christian Serre
Journal: Advanced Healthcare Materials (2024)

Over the past two decades, iron-based metal-organic frameworks (Fe-MOFs) have attracted significant research interest in biomedicine due to their low toxicity, tunable degradability, substantial drug loading capacity, versatile structures, and multimodal functionalities. Despite their great potential, the transition of Fe-MOFs-based composites from laboratory research to clinical products remains challenging. This review evaluates the key properties that distinguish Fe-MOFs from other MOFs and highlights recent advances in synthesis routes, surface engineering, and shaping technologies. In particular, it focuses on their applications in biosensing, antimicrobial, and anticancer therapies. In addition, the review emphasizes the need to develop scalable, environmentally friendly, and cost-effective production methods for additional Fe-MOFs to meet the specific requirements of various biomedical applications. Despite the ability of Fe-MOFs-based composites to combine therapies, significant hurdles still remain, including the need for a deeper understanding of their therapeutic mechanisms and potential risks of resistance and overdose. Systematically addressing these challenges could significantly enhance the prospects of Fe-MOFs in biomedicine and potentially facilitate their integration into mainstream clinical practice.
Recent Development of Nanozymes for Combating Bacterial Drug Resistance: A Review
Authors: Lingping Xie, Haoyue Wu, Yuanfeng Li, Linqi Shi, Yong Liu
Journal: Advanced Healthcare Materials (2024)

The World Health Organization has warned that without effective action, deaths from drug-resistant bacteria can exceed 10 million annually, making it the leading cause of death. Conventional antibiotics are becoming less effective due to rapid bacterial drug resistance and slowed new antibiotic development, necessitating new strategies. Recently, materials with catalytic/enzymatic properties, known as nanozymes, have been developed, inspired by natural enzymes essential for bacterial eradication. Unlike recent literature reviews that broadly cover nanozyme design and biomedical applications, this review focuses on the latest advancements in nanozymes for combating bacterial drug resistance, emphasizing their design, structural characteristics, applications in combination therapy, and future prospects. This approach aims to promote nanozyme development for combating bacterial drug resistance, especially towards clinical translation.