tbuckley/cabot-search huggingface dataset:
Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches
Authors: Matthew T Warkentin, Hamad Al-Sawaihey, Stephen Lam, Geoffrey Liu, Brenda Diergaarde, Jian-Min Yuan, David O Wilson, Sukhinder Atkar-Khattra, Benjamin Grant, Yonathan Brhane, Elham Khodayari-Moez, Kiera R Murison, Martin C Tammemagi, Kieran R Campbell, Rayjean J Hung
Journal: Thorax (2024)

Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen.
Historical perspective and future directions: computational science in immuno-oncology
Authors: Cora A Ricker, Kevin Meli, Eliezer M Van Allen
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immuno-oncology holds promise for transforming patient care having achieved durable clinical response rates across a variety of advanced and metastatic cancers. Despite these achievements, only a minority of patients respond to immunotherapy, underscoring the importance of elucidating molecular mechanisms responsible for response and resistance to inform the development and selection of treatments. Breakthroughs in molecular sequencing technologies have led to the generation of an immense amount of genomic and transcriptomic sequencing data that can be mined to uncover complex tumor-immune interactions using computational tools. In this review, we discuss existing and emerging computational methods that contextualize the composition and functional state of the tumor microenvironment, infer the reactivity and clonal dynamics from reconstructed immune cell receptor repertoires, and predict the antigenic landscape for immune cell recognition. We further describe the advantage of multi-omics analyses for capturing multidimensional relationships and artificial intelligence techniques for integrating omics data with histopathological and radiological images to encapsulate patterns of treatment response and tumor-immune biology. Finally, we discuss key challenges impeding their widespread use and clinical application and conclude with future perspectives. We are hopeful that this review will both serve as a guide for prospective researchers seeking to use existing tools for scientific discoveries and inspire the optimization or development of novel tools to enhance precision, ultimately expediting advancements in immunotherapy that improve patient survival and quality of life.
Revisiting the performance of cyst fluid carcinoembryonic antigen as a diagnostic marker for pancreatic mucinous cysts: a comprehensive 20-year institutional review
Authors: Melanie C Kwan, Martha Bishop Pitman, Carlos Fernandez-del Castillo, M Lisa Zhang
Journal: Gut (2024)

Objective Elevated pancreatic cyst fluid carcinoembryonic antigen (CEA) has been routinely used to classify mucinous cysts. This study incorporates original data that established the CEA ≥192 ng/mL threshold with over 20 years of additional data and reassesses the diagnostic performance of CEA for differentiating mucinous from non-mucinous cysts. Design 1169 pancreatic cysts (1999–2021) with CEA results were identified. 394 cases had histological confirmation as the diagnostic standard. Additionally, 237 cysts without histological confirmation demonstrated KRAS , GNAS , or RNF43 mutations by molecular testing and were combined with the histologically confirmed cysts for separate analysis on a total cohort of 631 cysts. Results Median CEA was significantly higher in mucinous cysts (323.9 ng/mL, n=314) versus non-mucinous cysts (204.6 ng/mL, n=80) (p&lt;0.001). Receiver operating characteristic curve analysis demonstrated an optimal CEA cut-off of 20 ng/mL (area under the curve: 80%), though the specificity was lower than desired (sensitivity 89%, specificity 64%). At the previously established threshold of 192 ng/mL, sensitivity and specificity were 56% and 78%, respectively. To achieve a specificity of 85% as originally reported, a CEA threshold of 250 ng/mL was needed; the 13 false positive cases at this threshold included 4 benign simple cysts, 2 squamoid cysts, 1 serous cystadenoma, 1 lymphoepithelial cyst and 5 more uncommon entities. All results remained similar within the total cohort after including additional cases with KRAS/GNAS/RNF43 mutations only. Conclusion Cyst fluid CEA continues to be a useful test in the diagnosis of mucinous pancreatic cysts but does not appear as specific as previously reported. Raising the CEA threshold to 250 ng/mL to maintain specificity for differentiating mucinous from non-mucinous cysts may be considered.
Outcomes of patients with multiple myeloma and 1q gain/amplification receiving autologous hematopoietic stem cell transplant: the MD Anderson cancer center experience
Authors: Oren Pasvolsky, Sassine Ghanem, Denái R. Milton, Mikael Rauf, Mark R. Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Yosra Aljawai, Hina N. Khan, Partow Kebriaei, Hans C. Lee, Krina K. Patel, Sheeba K. Thomas, Donna M. Weber, Robert Z. Orlowski, Elizabeth J. Shpall, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Blood Cancer Journal (2024)

The prognostic impact of additional copies of chromosome 1q (1q + ) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008-2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p < 0.001), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, p = 0.030, 2.33, p = 0.023 and 3.00, p = 0.047, respectively). In conclusion, patients with 1q+ NDMM, especially 1q amplification, have inferior survival outcomes compared to standard-risk disease after upfront autoSCT, though outcomes are better than other high-risk cytogenetic abnormalities.
Treatment of non-constipated irritable bowel syndrome with the histamine 1 receptor antagonist ebastine: a randomised, double-blind, placebo-controlled trial
Authors: Lisse Decraecker, Danny De Looze, David P Hirsch, Heiko De Schepper, Joris Arts, Philip Caenepeel, Albert J Bredenoord, Jeroen Kolkman, Koen Bellens, Kim Van Beek, Fedrica Pia, Willy Peetermans, Tim Vanuytsel, Alexandre Denadai-Souza, Ann Belmans, Guy Boeckxstaens
Journal: Gut (2024)

We evaluated the histamine 1 receptor antagonist ebastine as a potential treatment for patients with non-constipated irritable bowel syndrome (IBS) in a randomised, placebo-controlled phase 2 study.
Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis
Authors: Kang-Gu Lee, Bong-Ki Hong, Saseong Lee, Naeun Lee, Seung-Whan Kim, Donghyun Kim, Wan-Uk Kim
Journal: Cellular and Molecular Immunology (2024)

Abstract Transcriptional coactivators regulate the rate of gene expression in the nucleus. Nuclear receptor coactivator 6 (NCOA6), a coactivator, has been implicated in embryonic development, metabolism, and cancer pathogenesis, but its role in innate immunity and inflammatory diseases remains unclear. Here, we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions. Unexpectedly, nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC, forming cytoplasmic specks. Mechanistically, NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3, promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1β and active caspase-1. Of note, Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3 R258W gain-of-function mutation in macrophages. Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases, folic-induced acute tubular necrosis and crystal-induced arthritis, in mice. Consistent with these findings, NCOA6 was highly expressed in macrophages derived from gout patients, and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results. Conclusively, NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases, including gout.
Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation
Authors: Chao Ma, Peng Chen, Jishan Du, Lu Wang, Ning Lu, Jiaojun Sun, Xu Qilong, Yu Wang, Liping Dou, Dai-Hong Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need. Methods A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×10 3 CMV-TCR-T cells/kg body weight per dose to 5×10 5 CMV-TCR-T cells/kg per dose. Results Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3–7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1–4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells. Conclusions Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT. Trial registration number ClinicalTrials.gov Registry ( NCT05140187 ).
VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial
Authors: Kelley Coffman-D'Annibale, Yuta Myojin, Cecilia Monge, Changqing Xie, Donna Mabry Hrones, Bradford J Wood, Elliot B Levy, David Kleiner, William Douglas Figg, Seth M Steinberg, Bernadette Redd, Tim F Greten
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response. Methods This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×10 13 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood. Results Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1 high Ki67 high CD8 + T cells and HLA-DR high T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs. Conclusion In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8 + T cells systemically that was poorly sustained. Trial registration number NCT04166383 .
Clinical and exercise professional opinion on designing a postpartum return-to-running training programme: an international Delphi study and consensus statement
Authors: Rita E Deering, Gráinne M. Donnelly, Emma Brockwell, Kari Bo, Margie H Davenport, Marlize De Vivo, Sinead Dufour, Lori Forner, Hayley Mills, Isabel S Moore, Amanda Olson, Shefali Mathur Christopher
Journal: British Journal of Sports Medicine (2024)

Returning to running postpartum presents challenges such as musculoskeletal pain and pelvic floor dysfunction for some females, but there is little guidance on developing and progressing postpartum training programmes. This study aims to establish expert consensus recommendations on designing and modifying a postpartum return-to-running training programme, highlight costs and access to qualified professionals as potential barriers and discuss clinical, research and sports policy implications. A three-round Delphi survey of clinical and exercise professionals working with postpartum runners was conducted. Round I consisted of open-ended questions related to designing the training plan, modifications based on biopsychosocial factors, key muscle groups to train and referral and payment sources. Rounds II and III involved Likert-scale voting to identify consensus (≥75% agreement). 118 participants completed Round I, 107 completed Round II (response rate 90.6%) and 95 completed Round III (response rate 80.5%). Consensus was reached in 42/47 (89%) statements, including recommendations for a period of relative rest, gradual increases in duration and intensity, starting with a walk-run protocol and incorporating strength training. Training should be modified based on musculoskeletal or pelvic symptoms, sleep, mental health, lactation or energy availability concerns. Cost and access to experienced postpartum running professionals were identified as potential barriers for runners to receive care. Consensus recommendations for a postpartum return-to-running programme include an individualised exercise prescription, gradual increases in physical activity, walk-run protocols and targeted muscle strengthening. Further research and improved access to clinical and exercise professionals are needed to inform and facilitate best practices.
Protecting Human and Animal Health: The Road from Animal Models to New Approach Methods
Authors: Barbara L.F. Kaplan, Alan M. Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B. Knudsen, M. Sue Marty, Sonya K. Sobrian, Suzanne C. Fitzpatrick, Marcia H. Ratner, Donna L. Mendrick
Journal: Pharmacological Reviews (2024)

<h3></h3> Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used to understand the effects and mechanisms of drugs or chemicals, with specific focus on applying the 3Rs. Although progress has been made in several areas with NAMs, complete replacement of animal models with NAMs is not yet attainable. The road to NAMs requires additional development, increased use, and, for regulatory decision making, usually formal validation. Moreover, it is likely that replacement of animal models with NAMs will require multiple assays to ensure sufficient biologic coverage. The purpose of this manuscript is to provide a balanced view of the current state of the use of animal models and NAMs as approaches to development, safety, efficacy, and toxicity testing of drugs and chemicals. Animals do not provide all needed information nor do NAMs, but each can elucidate key pieces of the puzzle of human and animal biology and contribute to the goal of protecting human and animal health. <h3>Significance Statement</h3> Data from traditional animal studies have predominantly been used to inform human health safety and efficacy. Although it is unlikely that all animal studies will be able to be replaced, with the continued advancement in new approach methods (NAMs), it is possible that sometime in the future, NAMs will likely be an important component by which the discovery, efficacy, and toxicity testing of drugs and chemicals is conducted and regulatory decisions are made.
Prophylactic treatment with <i>Bacteroides uniformis</i> and <i>Bifidobacterium bifidum</i> counteracts hepatic NK cell immune tolerance in nonalcoholic steatohepatitis induced by high fat diet
Authors: Jingyuan Xu, Qiaoyun Xia, Ting Wu, Yong Shao, Yatao Wang, Nuyun Jin, Peiying Tian, Longyun Wu, Xiaolan Lu
Journal: Gut Microbes (2024)

Hepatic immunity is one of the driving forces for the development of nonalcoholic steatohepatitis (NASH), and targeting gut microbiota is believed to affect the hepatic immune constitution. Here, we aimed to investigate the hepatic immunological state in NASH, with a specific emphasis on natural killer (NK) cells. In addition, we aimed to identify the contributing species that target hepatic immunity to provide new directions and support the feasibility of immunotherapy for NASH. A possible NASH population was determined by combination of long-term severe fatty liver, metabolic disorders and increased serum CK18 to detect serum immune factors and gut microbiota. NASH was induced in mice fed a high-fat diet to verify the prophylactic effect of the functional species on the immunopathology and development of NASH. Hepatic immunologic state was examined, and the effector functions of NK cells were detected. Hepatic transcriptome, proteomic, and fecal metagenome were performed. We observed a statistical increase in serum IL-10 (p < 0.001) and non-statistical decrease in interferon-γ and IL-6 in NASH population, hinting at the possibility of immune tolerance. Fecal Bacteroides uniformis and Bifidobacterium bifidum were abundant in healthy population but depleted in NASH patients. In NASH mice, hepatic CD8+T cells, macrophages, and dendritic cells were increased (p < 0.01), and NK cells were inhibited, which were identified with decreased granzyme B (p < 0.05). Bacteroides uniformis and Bifidobacterium bifidum improved hepatic pathological and metabolic cues, increased hepatic NK cells and reduced macrophages (p < 0.05). Bacteroides uniformis also restored hepatic NK cell function, which was identified as increased CD107a (p < 0.05). Transcriptional and translational profiling revealed that the functional species might restore the function of hepatic NK cells through multiple pathways, such as reduction of inhibitory molecules in NK cells. Bacteroides uniformis and Bifidobacterium bifidum are novel prophylactics for NASH that restore the impaired function of hepatic NK cells.