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  • 1
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    Online Resource
    Clonal dynamics and Stereo-seq resolve origin and phenotypic plasticity of adenosquamous carcinoma
    Springer Science and Business Media LLC ; 2023
    In:  npj Precision Oncology Vol. 7, No. 1 ( 2023-08-26)
    Details
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2023-08-26)
    Abstract: The genomic origin and development of the biphasic lung adenosquamous carcinoma (ASC) remain inconclusive. Here, we derived potential evolutionary trajectory of ASC through whole-exome sequencing, Stereo-seq, and patient-derived xenografts. We showed that EGFR and MET activating mutations were the main drivers in ASCs. Phylogenetically, these drivers and passenger mutations found in both components were trunk clonal events, confirming monoclonal origination. Comparison of multiple lesions also revealed closer genomic distance between lymph node metastases and the ASC component with the same phenotype. However, as mutational signatures of EGFR -positive lung squamous carcinomas (LUSCs) were more comparable to EGFR -positive ASCs than to wild-type LUSCs, we postulated different origination of these LUSCs, with ASC being the potential intermediate state of driver-positive LUSCs. Spatial transcriptomic profiling inferred transformation from adenocarcinoma to squamous cell carcinoma, which was then histologically captured in vivo. Together, our results explained the development of ASC and provided insights into future clinical decisions.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    URL: Article
    DOI: 10.1038/s41698-023-00430-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2891458-2
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  • 2
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    Multi-dimensional fragmentomic assay for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Hematology & Oncology Vol. 14, No. 1 ( 2021-12)
    Details
    In: Journal of Hematology & Oncology, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2021-12)
    Abstract: Previous studies on liquid biopsy-based early detection of advanced colorectal adenoma (advCRA) or adenocarcinoma (CRC) were limited by low sensitivity. We performed a prospective study to establish an integrated model using fragmentomic profiles of plasma cell-free DNA (cfDNA) for accurately and cost-effectively detecting early-stage CRC and advCRA. The training cohort enrolled 310 participants, including 149 early-stage CRC patients, 46 advCRA patients and 115 healthy controls. Plasma cfDNA samples were prepared for whole-genome sequencing. An ensemble stacked model differentiating healthy controls from advCRA/early-stage CRC patients was trained using five machine learning models and five cfDNA fragmentomic features based on the training cohort. The model was subsequently validated using an independent test cohort ( N  = 311; including 149 early-stage CRC, 46 advCRA and 116 healthy controls). Our model showed an area under the curve (AUC) of 0.988 for differentiating advCRA/early-stage CRC patients from healthy individuals in an independent test cohort. The model performed even better for identifying early-stage CRC (AUC 0.990) compared to advCRA (AUC 0.982). At 94.8% specificity, the sensitivities for detecting advCRA and early-stage CRC reached 95.7% and 98.0% (0: 94.1%; I: 98.5%), respectively. Promisingly, the detection sensitivity has reached 100% and 97.6% in early-stage CRC patients with negative fecal occult or CEA blood test results, respectively. Finally, our model maintained promising performances (AUC: 0.982, 94.4% sensitivity at 94.8% specificity) even when sequencing depth was down-sampled to 1X. Our integrated predictive model demonstrated an unprecedented detection sensitivity for advCRA and early-stage CRC, shedding light on more accurate noninvasive CRC screening in clinical practice.
    Type of Medium: Online Resource
    ISSN: 1756-8722
    URL: Article
    DOI: 10.1186/s13045-021-01189-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2429631-4
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  • 3
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    Mechanisms of resistance to tyrosine kinase inhibitor treatments in patients with ROS1 fusion-positive non-small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 9062-9062
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 9062-9062
    Abstract: 9062 Background: ROS1 rearrangement was found in about 1% non-small cell lung cancer (NSCLC), and the fusion proteins created during this process will result in the successive activation of the ROS1 kinase domain. NSCLC patients with ROS1 gene fusions were considered a unique subtype highly sensitive to related tyrosine kinase inhibitor (TKI) treatments. However, the acquired TKI resistance was the major hurdle preventing patients from getting prolonged treatment benefits. Methods: 107 patients diagnosed with advanced or metastatic NSCLC harboring ROS1 fusion were retrospectively recruited. All patients were treated with crizotinib as first-line treatment, and 21 patients received lorlatinib after crizotinib progression. Samples were collected at baseline, after crizotinib progression, and after lorlatinib progression, which all underwent targeted DNA sequencing. TKIs binding to mutated ROS1 fusion proteins was simulated using molecular dynamics simulations. Results: The most witnessed fusion partner of ROS1 was CD74 (58%), followed by SDC4 (14%), EZR (11%), and SLC34A2 (9%). The median progression-free survival was 12.9 months for crizotinib and 6.4 months for lorlatinib. Patients with CD74-ROS1 and SLC34A2-ROS1 had significantly longer PFS than those with other ROS1 fusion types when treated with crizotinib. Patients with baseline TP53 mutations showed worse PFS compared to TP53 wild-type (WT) patients (P 〈 0.001, HR: 0.19, 95%CI: 0.09-0.39) under crizotinib treatment. An accumulation of both on-target (baseline vs. post-crizotinib vs. post-lorlatinib: 0% vs. 43% vs. 62%) and off-target resistant mutations (baseline vs. post-crizotinib vs. post-lorlatinib: 22% vs. 26% vs. 43%) after multiple TKI treatments was observed. A total of ten on-target resistance mutations were detected after TKI therapies, with 4 first-reported mutations (ROS1 L2010M, G1957A, D1988N, L1982V). According to the molecular dynamics simulation results, ROS1 L2010M mutations (happening in the ROS1 kinase ATP binding cassette) maybe resistant to lorlatinib, entrectinib, cabozantinib, and crizotinib. ROS1 G1957A may lead to resistance to cabozantinib. Moreover, all four novel on-target mutations may lead to resistance to crizotinib. Conclusions: In summary, CD74- and SLC34A2-ROS1 patients showed better crizotinib efficacy with different resistance mutation patterns. Patients of these subtypes are potential beneficiaries of molecular testing after crizotinib progression, directing future treatment strategies. Multiple TKI treatments may lead to the accumulation of both on-target and off-target resistance mutations. In addition, 4 novel ROS1 on-target mutations identified underwent molecular dynamics simulations, unveiling potential resistance to different TKIs, which can provide vital information for future ROS1 fusion-positive NSCLC patient treatment selections.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.9062
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study
    Public Library of Science (PLoS) ; 2021
    In:  PLOS Medicine Vol. 18, No. 8 ( 2021-8-31), p. e1003741-
    Details
    In: PLOS Medicine, Public Library of Science (PLoS), Vol. 18, No. 8 ( 2021-8-31), p. e1003741-
    Abstract: For locally advanced rectal cancer (LARC) patients who receive neoadjuvant chemoradiotherapy (nCRT), there are no reliable indicators to accurately predict pathological complete response (pCR) before surgery. For patients with clinical complete response (cCR), a “Watch and Wait” (W & W) approach can be adopted to improve quality of life. However, W & W approach may increase the recurrence risk in patients who are judged to be cCR but have minimal residual disease (MRD). Magnetic resonance imaging (MRI) is a major tool to evaluate response to nCRT; however, its ability to predict pCR needs to be improved. In this prospective cohort study, we explored the value of circulating tumor DNA (ctDNA) in combination with MRI in the prediction of pCR before surgery and investigated the utility of ctDNA in risk stratification and prognostic prediction for patients undergoing nCRT and total mesorectal excision (TME). Methods and findings We recruited 119 Chinese LARC patients (cT3-4/N0-2/M0; median age of 57; 85 males) who were treated with nCRT plus TME at Fudan University Shanghai Cancer Center (China) from February 7, 2016 to October 31, 2017. Plasma samples at baseline, during nCRT, and after surgery were collected. A total of 531 plasma samples were collected and subjected to deep targeted panel sequencing of 422 cancer-related genes. The association among ctDNA status, treatment response, and prognosis was analyzed. The performance of ctDNA alone, MRI alone, and combining ctDNA with MRI was evaluated for their ability to predict pCR/non-pCR. Ranging from complete tumor regression (pathological tumor regression grade 0; pTRG0) to poor regression (pTRG3), the ctDNA clearance rate during nCRT showed a significant decreasing trend (95.7%, 77.8%, 71.1%, and 66.7% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.008), while the detection rate of acquired mutations in ctDNA showed an increasing trend (3.8%, 8.3%, 19.2%, and 23.1% in pTRG 0, 1, 2, and 3 groups, respectively, P = 0.02). Univariable logistic regression showed that ctDNA clearance was associated with a low probability of non-pCR (odds ratio = 0.11, 95% confidence interval [95% CI] = 0.01 to 0.6, P = 0.04). A risk score predictive model, which incorporated both ctDNA (i.e., features of baseline ctDNA, ctDNA clearance, and acquired mutation status) and MRI tumor regression grade (mrTRG), was developed and demonstrated improved performance in predicting pCR/non-pCR (area under the curve [AUC] = 0.886, 95% CI = 0.810 to 0.962) compared with models derived from only ctDNA (AUC = 0.818, 95% CI = 0.725 to 0.912) or only mrTRG (AUC = 0.729, 95% CI = 0.641 to 0.816). The detection of potential colorectal cancer (CRC) driver genes in ctDNA after nCRT indicated a significantly worse recurrence-free survival (RFS) (hazard ratio [HR] = 9.29, 95% CI = 3.74 to 23.10, P 〈 0.001). Patients with detectable driver mutations and positive high-risk feature (HR_feature) after surgery had the highest recurrence risk (HR = 90.29, 95% CI = 17.01 to 479.26, P 〈 0.001). Limitations include relatively small sample size, lack of independent external validation, no serial ctDNA testing after surgery, and a relatively short follow-up period. Conclusions The model combining ctDNA and MRI improved the predictive performance compared with the models derived from individual information, and combining ctDNA with HR_feature can stratify patients with a high risk of recurrence. Therefore, ctDNA can supplement MRI to better predict nCRT response, and it could potentially help patient selection for nonoperative management and guide the treatment strategy for those with different recurrence risks.
    Type of Medium: Online Resource
    ISSN: 1549-1676
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    DOI: 10.1371/journal.pmed.1003741
    DOI: 10.1371/journal.pmed.1003741.g001
    DOI: 10.1371/journal.pmed.1003741.g002
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    DOI: 10.1371/journal.pmed.1003741.t001
    DOI: 10.1371/journal.pmed.1003741.s001
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    DOI: 10.1371/journal.pmed.1003741.s015
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2021
    detail.hit.zdb_id: 2164823-2
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  • 5
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    Ultrasensitive and affordable assay for early detection of primary liver cancer using plasma cell‐free DNA fragmentomics
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Hepatology Vol. 76, No. 2 ( 2022-08), p. 317-329
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 76, No. 2 ( 2022-08), p. 317-329
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.32308
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1472120-X
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  • 6
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    Letter to the Editor: An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection
    Springer Science and Business Media LLC ; 2022
    In:  Molecular Cancer Vol. 21, No. 1 ( 2022-12)
    Details
    In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2022-12)
    Abstract: Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients ( N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.
    Type of Medium: Online Resource
    ISSN: 1476-4598
    URL: Article
    DOI: 10.1186/s12943-022-01594-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2091373-4
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  • 7
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    ctDNA as a potential prognostic marker for locally advanced rectal cancer patients with ‘watch and wait’ approach.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 3544-3544
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3544-3544
    Abstract: 3544 Background: ‘Watch and Wait’ policy has currently led to growing interest for organ-preservation after neoadjuvant chemoradiation (nCRT) to improve quality of life. However, how to predict and select patients who may achieve clinical complete response is still an unsolved issue. We conducted a pilot study to evaluate the potential role of ctDNA as a biomarker to predict treatment outcome and improve risk stratification in locally advanced rectal cancer (LARC). Methods: In this study, we recruited 119 patients with LARC receiving nCRT. 595 serial plasma samples were collected at d0, d15, d25 of radiotherapy as well before and 7 days post surgery. The level of ctDNA was calculated by dynamic monitoring the mutant allele frequency of somatic mutations in plasma. Plasma and tissue samples were subjected to targeted-NGS using a 422 cancer-related genes panel. We followed up patients with concomitant CT until disease progression or death. Results: Detected mutation of TP53 and APC gene in pre-treatment samples was negatively correlated with patients’ response to nCRT. Alterations in homologous recombination and adherens junction pathways were associated with a better response (P 〈 0.05). Detection of pre-treatment mutations in any time points during nCRT was significantly (P = 0.03) decreased from TRG3 to TRG0 group (33%, 29%, 22% and 4%, respectively); while detection of acquired mutations showed an opposite trend (P = 0.04). A predictive model based on support vector machine was developed for prediction of pCR achieving a mean AUC of 0.85 assessed by repeated cross validation. Further, detection of pre-treatment mutations after completion of nCRT was significantly associated with worse disease-free survival (DFS) (P 〈 0.05). Through tracking clonal extinction, persistence and emergence, patients were grouped into four evolutionary subtypes with distinct TRG and DFS. Conclusions: Our data showed the prognostic value of ctDNA on DFS. Dynamic monitoring of ctDNA can be used to predict TRG and prognosis in LARC patients receiving nCRT. ctDNA sequencing depicts the evolutionary trajectories of sensitive and resistant clones during nCRT in LARC. CtDNA could potentially be used to guide patient selection for W & W strategy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.3544
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 8
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    Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer
    Elsevier BV ; 2019
    In:  Lung Cancer Vol. 127 ( 2019-01), p. 19-24
    Details
    In: Lung Cancer, Elsevier BV, Vol. 127 ( 2019-01), p. 19-24
    Type of Medium: Online Resource
    ISSN: 0169-5002
    URL: Article
    DOI: 10.1016/j.lungcan.2018.11.024
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2025812-4
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  • 9
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    A review of security issues and solutions for precision health in Internet-of-Medical-Things systems
    EDP Sciences ; 2023
    In:  Security and Safety Vol. 2 ( 2023), p. 2022010-
    Details
    In: Security and Safety, EDP Sciences, Vol. 2 ( 2023), p. 2022010-
    Abstract: Precision medicine provides a holistic perspective of an individual’s health, including genetic, environmental, and lifestyle aspects to realize individualized therapy. The development of the internet of things (IoT) devices, the widespread emergence of electronic medical records (EMR), and the rapid progress of cloud computing and artificial intelligence provide an opportunity to collect healthcare big data throughout the lifespan and analyze the disease risk at all stages of life. Thus, the focus of precision medicine is shifting from treatment toward prediction and prevention, i.e. , precision health. To this end, various types of data such as omics, imaging, EMR, continuous physiological monitoring, lifestyle, and environmental information, need to be collected, tracked, managed and shared. Thus, internet-of-medical things (IoMT) is crucial for assimilating the health systems, applications, services, and devices that can improve the speed and accuracy of diagnosis and treatments along with real-time monitoring and modification of patient behavior as well as health status. However, security has emerged as a growing concern owing to the proliferation of IoMT devices. The increasing interconnectivity of IoMT-enabled devices with health data reception, transmission, and processing significantly increases the number of potential vulnerabilities within a system. To address the security issues of precision health in IoMT systems, this study reviews the state-of-the-art techniques and schemes from the perspective of a hierarchical system architecture. We present an IoMT system model comprising three layers: the sensing layer, network layer, and cloud infrastructure layer. In particular, we discuss the vulnerabilities and threats to security in each layer and review the existing security techniques and schemes corresponding to the system components along with their functionalities. Owing to the unique nature of biometric features in medical and health services, we highlight the biometrics-based technologies applied in IoMT systems, which contribute toward a considerable difference between the security solutions of existing IoT systems. Furthermore, we summarize the challenges and future research directions of IoMT systems to ensure an improved and more secure future of precision health.
    Type of Medium: Online Resource
    ISSN: 2826-1275
    URL: Article
    DOI: 10.1051/sands/2022010
    Language: English
    Publisher: EDP Sciences
    Publication Date: 2023
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  • 10
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    A 62-Year-Old Woman With Pulmonary Tuberculosis Complicating Left Ventricular Thrombus and Splenic Infarction
    Elsevier BV ; 2016
    In:  Chest Vol. 149, No. 4 ( 2016-04), p. A65-
    Details
    In: Chest, Elsevier BV, Vol. 149, No. 4 ( 2016-04), p. A65-
    Type of Medium: Online Resource
    ISSN: 0012-3692
    URL: Article
    DOI: 10.1016/j.chest.2016.02.069
    RVK:
    XA 36340
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 2007244-2
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