tbuckley/cabot-search huggingface dataset:
Re: Characteristics of a cost-effective blood test for colorectal cancer screening
Authors: Qiang Hu, Xiyin Yang, Yuanshui Sun
Journal: JNCI Journal of the National Cancer Institute (2024)

We read with great interest the recent study evaluating the effectiveness and costeffectiveness of blood-based biomarker screening for colorectal cancer (CRC) compared to established screening methods like fecal immunochemical testing (FIT) and colonoscopy. 1The authors have contributed an important analysis in a rapidly evolving field.Nevertheless, we would like to provide some insights and observations regarding certain methodological choices and assumptions.First, a notable area for further exploration is the influence of genetic and environmental risk heterogeneity on the cost-effectiveness of blood-based biomarker screening.The current study applies a uniform model to a simulated average-risk population; however, emerging research suggests that genetic predispositions and lifestyle factors, such as diet and smoking history, markedly alter CRC risk and could
Response to Hu, Yang, and Sun
Authors: Pedro Nascimento de Lima, Carolyn M Rutter, Rosita van den Puttelaar, Anne I Hahn, Jonathan Ozik, Nicholson Collier, Ann G Zauber, Iris Lansdorp-Vogelaar, John M Inadomi
Journal: JNCI Journal of the National Cancer Institute (2024)

We appreciate the opportunity to reply to Hu et al.'s Correspondence [1] and clarify our findings regarding performance characteristics and costs that could render blood-based biomarker tests cost-effective for colorectal cancer (CRC) screening when compared to standard screening tests.Our analysis focused on establishing the minimum performance requirements for average-risk populations, to address whether new blood tests should be offered to the population at large, a central question for key US stakeholders.This is an important first step.While we agree that it would be interesting to examine targeted use of blood tests based on patient risk -such as those with genetic or environmental risk factors -it is unlikely that a blood test that is insensitive to precursor lesions would be useful for screening high-risk populations as these individuals would likely be screened and surveilled through colonoscopy.Hu et al. suggest that we did not place enough emphasis on the detection of advanced adenomas and cumulative false positives, but our analysis did underscore the importance of detecting advanced adenomas and considered the effects of false positives.We demonstrated that increasing sensitivity to advanced adenomas from 10%
<i>Desulfovibrio vulgaris</i> flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway
Authors: Yue Dong, Fanyi Meng, Jingyi Wang, Jingge Wei, Kexin Zhang, Siqi Qin, Mengfan Li, Fucheng Wang, Bangmao Wang, Tianyu Liu, Weilong Zhong, Hailong Cao
Journal: Gut Microbes (2024)

The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. Desulfovibrio vulgaris (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found Desulfovibrio was abundant in high-fat diet-induced Apcmin/+ mice, and DSV, a member of Desulfovibrio, triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that D. vulgaris flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.
Outcomes of Patients With Treated Secondary Acute Myeloid Leukemia: A High‐Risk Subtype That Warrants an Independent Prognostic Designation
Authors: Jayastu Senapati, Hagop M. Kantarjian, Fadi G. Haddad, Nicholas J. Short, Gautam Borthakur, Rashmi Kanagal‐Shamanna, Guilin Tang, Elias Jabbour, Courtney D. DiNardo, Naval Daver, Guillermo Montalban‐Bravo, Vishrut Shah, Amin Alousi, Elizabeth Shpall, Uday Popat, Guillermo Garcia‐Manero, Farhad Ravandi, Tapan M. Kadia
Journal: American Journal of Hematology (2024)

ABSTRACT Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19–94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS‐MPN. Additionally, 149 patients (22%) had prior therapy for nonmyeloid malignancies. Among 497 evaluable patients, 289 (58%) had adverse‐risk (AR) cytogenetics, 34% had TP53 mutation/s, and 71% were classified as AR by the ELN 2017 criteria. Most patients (67%) received low‐intensity therapy (LIT) for AML, and 27% were treated with venetoclax. The overall response rate was 37%, and venetoclax improved the odds of response (OR = 2.5, 95% CI 1.6–3.7) in LIT–treated patients. At a median follow‐up of 43 months, the median relapse‐free survival (RFS) and overall survival (OS) were 4.6 and 4.8 months, respectively. Multivariate analysis showed that prior therapy for nonmyeloid disorders (HR = 1.30), ≥ 2 lines of therapy for antecedent myeloid disorders (HR = 1.23), and ELN AR risk (HR = 1.47) increased the hazards of death, while HSCT (HR = 0.50) was beneficial and validated on gradient‐boosted regression. TS‐AML is associated with poor outcomes irrespective of AML genomics and treatment, highlighting the need for its inclusion as an independent AR category for accurate prognostication and clinical trial reporting.
Epigenetic alterations and memory: key players in the development/progression of chronic kidney disease promoted by acute kidney injury and diabetes
Authors: Imari Mimura, Zhuo Chen, Rama Natarajan
Journal: Kidney International (2024)

Chronic kidney disease (CKD) is a highly prevalent global public health issue and can progress to renal failure. Survivors of acute kidney injury (AKI) have an increased risk of progressing to CKD by 8.8-fold and kidney failure by 3.1-fold. Further, 20%‒40% of individuals with diabetes will develop CKD, also known as diabetic kidney disease (DKD). Thus, preventing these kidney diseases can positively impact quality-of-life and life-expectancy outcomes for affected individuals. Frequent episodes of hyperglycemia and renal hypoxia are implicated in the pathophysiology of CKD. Prior periods of hyperglycemia/uncontrolled diabetes can result in development/progression of DKD even after achieving normoglycemia, a phenomenon known as metabolic memory or legacy effect. Similarly, in AKI, hypoxic memory is stored in renal cells even after recovery from the initial AKI episode and can transition to CKD. Epigenetic mechanisms involving DNA methylation, chromatin histone post-translational modifications and non-coding RNAs are implicated in both metabolic and hypoxic memory, collectively known as "epigenetic memory." This epigenetic memory is generally reversible and provides a therapeutic avenue to ameliorate persistent disease progression due to hyperglycemia and hypoxia and prevent/ameliorate CKD progression. Indeed, therapeutic strategies targeting epigenetic memory are effective at preventing CKD development/progression in experimental models of AKI and DKD. Here, we review the latest in-depth evidence for epigenetic features in DKD and AKI, and in epigenetic memories of AKI-to-CKD transition or DKD development and progression, followed by translational and clinical implications of these epigenetic changes for the treatment of these widespread kidney disorders.
North American Clinical Practice Guidelines for the Medical Management of Hidradenitis Suppurativa in Special Patient Populations
Authors: Raed Alhusayen, Serena Dienes, Megan Lam, Afsaneh Alavi, Ali Alikhan, Maria Aleshin, Emad Bahashwan, Steve Daveluy, Noah Goldfarb, Amit Garg, Wayne Gulliver, Tarannum Jaleel, Alexa B. Kimball, Mark G. Kirchhof, Joslyn Kirby, Joi Lenczowski, Hadar Lev-Tov, Michelle A. Lowes, Irene Lara-Corrales, Robert Micheletti, Martin Okun, Lauren Orenstein, Susan Poelman, Vincent Piguet, Martina Porter, Barry Resnik, Cathryn Sibbald, Vivian Shi, Christopher Sayed, Se Mang Wong, Andrea Zaenglein, Helene Veillette, Jennifer L. Hsiao, Haley B. Naik
Journal: Journal of the American Academy of Dermatology (2024)
Response to Fleshner et al., “Bridging the Gap in Acne Vulgaris Research for Skin of Color Patients: Response to: "Assessing the Inclusion of Post-Inflammatory Hyperpigmentation Outcomes in Acne Vulgaris Clinical Trials"
Authors: Alyssa Swearingen, Christine Olagun-Samuel, Prince Adotama
Journal: Journal of the American Academy of Dermatology (2024)
Bi2WO6@Cu2O-GOx Bio-Heterojunction Spray for Accelerating Chronic Diabetic Wound Repairment with Bilaterally Enhanced Sono-Catalysis and Glycolytic Inhibition Antisepsis
Authors: Yandong Wang, Fei Chang, Yutang Li, Fenglong Wang, Can Li, Hui Li, Yanyan Jiang
Journal: Biomaterials (2024)
Somatic mosaicism in genetic errors of immunity
Authors: Megan A Cooper
Journal: Journal of Allergy and Clinical Immunology (2024)

Genetic mosaicism in somatic cells can lead to the presence of pathogenic variants in a subset of immune cells causing genetic errors of immunity (GEI), often phenocopying germline inborn errors of immunity (IEI). Over the last two decades significant progress has been made in the identification of these disorders in patients, including discovery of new diseases. Diagnosis of disease-causing somatic mosaicism provides a target for treatment and monitoring of patients and has implications for genetic counseling. However, there continue to be barriers in the identification of somatic mosaicism, particularly for the clinical diagnosis of patients, based on the limitations of current diagnostic sequencing and analysis approaches. This review focuses on how somatic mosaicism can lead to GEI, the genes known to be associated with somatic GEI, and challenges in the field for accurate diagnosis of patients.
Update on inborn errors of immunity
Authors: Hanna IJspeert, Emily S J Edwards, Robyn E O'Hehir, Virgil A S H Dalm, Menno C van Zelm
Journal: Journal of Allergy and Clinical Immunology (2024)

Ever since the first description of an inherited immunodeficiency in 1952 in a boy with gammaglobulin deficiency, new insights have progressed rapidly in disorders that are now referred to as inborn errors of immunity (IEI). In a field where fundamental molecular biology, genetics, immune signaling and clinical care are tightly intertwined, 2022-2024 saw a multitude of advances. Here we report a selection of research updates with a main focus on (1) diagnosis and screening, (2) new genetic defects, (3) susceptibility to severe COVID-19 infection and impact of vaccination, and (4) treatment. Importantly, new pathogenic insights more rapidly impact on treatment outcomes, either through an earlier and more precise diagnosis, or through implementation of novel, personalized treatment. As the field is growing rapidly, awareness, communication and collaboration are key to improving treatment outcomes.
Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines
Authors: Danny M Cohn, Daniel F Soteres, Timothy J Craig, William R Lumry, Markus Magerl, Marc A Riedl, Paul K Audhya, Marcus Maurer, Jonathan A Bernstein
Journal: Journal of Allergy and Clinical Immunology (2024)

Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly. Subsequent post hoc analyses of clinical trial data alongside real-world evidence led to a paradigm shift. In 2013, the US HAE Association guidelines recommended that all attacks, irrespective of location or severity, be considered for treatment as early as possible after onset to minimize morbidity and mortality. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance.
A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate
Authors: Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D. Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki
Journal: Journal of Clinical Investigation (2024)

Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, antigenicity of most adjuvantic lipids are unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activates human T cells bearing a unique ɑβTCR. This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA sequencing using newly established CD1b-TMM tetramers revealed that TMM-specific T cells are present as CD4+ effector memory T cells in the periphery of uninfected donors, but express IFNγ, TNF and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells are detected in cord blood and PBMCs of non-BCG-vaccinated donors, but are expanded in active tuberculosis patients. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively-charged CDR3ɑ and long CDR3β regions. These results indicate that humans have a commonly-shared and pre-formed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.
CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer
Authors: Giulia Fracassi, Francesca Lorenzin, Francesco Orlando, Ubaldo Gioia, Giacomo D'Amato, Arnau S. Casaramona, Thomas Cantore, Davide Prandi, Frédéric R. Santer, Helmut Klocker, Fabrizio d’Adda di Fagagna, Joaquin Mateo, Francesca Demichelis
Journal: Journal of Clinical Investigation (2024)

PARP inhibitors (PARPi) have received regulatory approval for the treatment of several tumors, including prostate cancer (PCa), and demonstrate remarkable results in the treatment of castration-resistant prostate cancer (CRPC) patients characterized by defects in homologous recombination repair (HRR) genes. Preclinical studies showed that DNA repair genes (DRG) other than HRR genes may have therapeutic value in the context of PARPi. To this end, we performed multiple CRISPR/Cas9 screens in PCa cell lines using a custom sgRNA library targeting DRG combined with PARPi treatment. We identified LIG1, EME1, and FAAP24 losses as PARPi sensitizers and assessed their frequencies from 3 to 6% among CRPC patients. We showed that concomitant inactivation of LIG1 and PARP induced replication stress and DNA double-strand breaks, ultimately leading to apoptosis. This synthetic lethality (SL) is conserved across multiple tumor types (e.g., lung, breast, and colorectal), and its applicability might be extended to LIG1-functional tumors through a pharmacological combinatorial approach. Importantly, the sensitivity of LIG1-deficient cells to PARPi was confirmed in vivo. Altogether, our results argue for the relevance of determining the status of LIG1, and potentially other non-HRR DRG for CRPC patient stratification and provide evidence to expand their therapeutic options.
Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models
Authors: Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T. Olson, Christina C. Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M. Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S. Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S. Donald-Paladino, Jaylen M. Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Gu, Tinghu Zhang, Baoli Hu, Benjamin A. Nacev, Medard Ernest Kaiza, Alice H. Berger, Xuerui Wang, Jing Li, Xuejiao Sun, Yang Liu, Xiaoyang Zhang, Tullia C. Bruno, Nathanael S. Gray, Behnam Nabet, Kwok-Kin Wong, Hua Zhang
Journal: Journal of Clinical Investigation (2024)

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.
Erratum to “Adipose ADM2 ameliorates NAFLD via promotion of ceramide catabolism” [Acta Pharm Sin B 14 (2024) 4883-4898]
Authors: Pengcheng Wang, Song-Yang Zhang, YongQiang Dong, Guangyi Zeng, Huiying Liu, Xian Wang, Changtao Jiang, Yin Li
Journal: Acta Pharmaceutica Sinica B (2024)

[This corrects the article DOI: 10.1016/j.apsb.2024.09.010.].
Specialist training in infectious diseases in Europe
Authors: Jon Salmanton-García, António Guerra Maio, Jean Paul Stahl, Eoghan de Barra, Søren Jensen-Fangel, Carlo Torti, Christian Kraef, José M Miró, Annelies Verbon, Oliver A Cornely, Nick J Beeching
Journal: Clinical Microbiology and Infection (2024)

The objectives were to determine the structure of training programmes and assessment of physicians training to become infectious disease (ID) specialists in Europe in early 2024 and to document the provision of specialists, trainees and training centres in each country. Delegates to the ID Section and Board of the European Union of Medical Specialists entered national data on a web-based survey tool in late 2023-early 2024. Results were compared with European Union of Medical Specialists recommendations on the structure and content of postgraduate training in ID in Europe (2018), and to results of a similar survey in early 2021. Responses were received from all 35 countries; 27/35 (77%) recognize ID as an independent speciality and 7/35 (20%) as a subspeciality. Spain does not officially recognize the speciality. In Cyprus, Iceland, and Luxembourg, despite official recognition of the sub-/speciality, ID training must be completed abroad. Paediatric ID was recognized in 16/35 (46%) countries. The number of adult ID specialists varied from 78.8 per million inhabitants in Sweden to 0.6 in Germany. Only 7/31 (23%) national programmes provide the minimum recommended 6 months of training in medical microbiology. Assessment methods included logbooks/portfolios in 25/31 (81%), final examinations in 25/31 (81%) and workplace-based assessments in 21/31 (68%). There has been little change since 2021 in speciality status or in structure and content of training programmes across Europe. There have been large increases in training position numbers in several countries, possibly in response to COVID-19. Continued low compliance with the 2018 recommendations to increase exposure to medical microbiology during training highlights the slow pace of change. Logistic barriers to change and to harmonization across Europe remain and are discussed in the context of published concerns of trainees.
Mortality predictors and definition proposal for complicated coagulase-negative Staphylococcus bacteremia. A multicenter prospective cohort study
Authors: Benedetta Varisco, Pedro María Martínez Pérez-Crespo, Pilar Retamar-Gentil, Inmaculada López Hernandez, Ma Carmen Fariñas-Álvarez, Isabel Fernández-Natal, María Teresa Pérez-Rodríguez, Ane Josune Goikoetxea Aguirre, Juan Manuel Sánchez-Calvo, Luis Buzón Martín, Eva León-Jiménez, David Vinuesa García, José María Reguera-Iglesias, Alberto Bahamonde-Carrasco, Jonathan Fernández Suárez, Jesús Rodríguez-Baño, Luis Eduardo López-Cortés
Journal: Clinical Microbiology and Infection (2024)