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  • 1
    In: The Lancet, Elsevier BV, Vol. 395, No. 10234 ( 2020-05), p. 1417-1418
    Type of Medium: Online Resource
    ISSN: 0140-6736
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2067452-1
    detail.hit.zdb_id: 3306-6
    detail.hit.zdb_id: 1476593-7
    SSG: 5,21
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  • 2
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2021
    In:  Breast Cancer Research Vol. 23, No. 1 ( 2021-12)
    In: Breast Cancer Research, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2021-12)
    Abstract: A dual blockade against the novel immune checkpoint inhibitor lymphocyte activation gene-3 (LAG-3) and programmed cell death protein-1 (PD-1) is currently considered in advanced breast cancer. Nevertheless, PD-1 or LAG-3 expression within distant metastatic breast cancer tissue remains understudied. Methods To address this knowledge gap, we investigated the PD-1 and LAG-3 expression in combination with the CD8-based immune phenotype in intrapatient matched primary tumor distant metastases, representing 95 breast cancer patients with metastases occurring at four different anatomical locations. The immune phenotype was categorized into 2 categories: inflamed corresponding to the clinical category “hot” and exhausted or desert consistent with clinically “cold” tumors. Results Metastases of “cold” primary tumors always remained “cold” at their matched metastatic site. Expression of PD-1/LAG-3 was associated with a “hot” immune phenotype in both the primary tumors and metastases. We could not observe any association between the immune phenotype and the breast cancer molecular subtype. Brain and soft tissue metastases were more commonly inflamed with signs of exhaustion than other anatomical sites of metastases. Taken together, (i) the immune phenotype varied between sites of distant metastases, and (ii) PD-1 + /LAG-3 + was strongly associated with a “hot” immune phenotype and (iii) was most prevalent in brain and soft tissue metastases among distant metastases. Conclusions Our data strongly support an integrated analysis of the immune phenotype together with the PD-1/LAG-3 expression in distant metastases to identify patients with inflamed but exhausted tumors. This may eventually improve the stratification and likelihood for advanced breast cancer patients to profit from immunotherapy.
    Type of Medium: Online Resource
    ISSN: 1465-542X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041618-0
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  • 3
    In: Cell Reports Medicine, Elsevier BV, Vol. 4, No. 3 ( 2023-03), p. 100977-
    Type of Medium: Online Resource
    ISSN: 2666-3791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 3019420-9
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  • 4
    In: The Journal of Pathology: Clinical Research, Wiley, Vol. 10, No. 2 ( 2024-03)
    Abstract: Most invasive lobular breast carcinomas (ILBCs) are luminal‐type carcinomas with an HER2‐negative phenotype ( ERBB2 or HER2 un‐amplified) and CDH1 mutations. Rare variants include ERBB2 ‐amplified subtypes associated with an unfavorable prognosis and less response to anti‐HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2 ‐amplified ILBC and compared these characteristics with ERBB2 ‐unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin‐embedded formalin‐fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast‐specific markers was tested by immunohistochemistry (IHC). Hybrid capture‐based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2 ‐amplified ILBC had higher tumor stage ( p 〈 0.0001), more frequent positive nodal status ( p = 0.00022), more distant metastases ( p = 0.012), and higher histological grade ( p 〈 0.0001), and were more often hormone receptor negative ( p 〈 0.001) and more often SOX10 positive ( p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2 ‐unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2‐positive ILBC ( p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2 ‐amplified ILBC ( p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2 ‐amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12 , whereas ERBB2 sequence mutations occur only in ERBB2 ‐unamplified ILBC. CDK12 / ERBB2 co‐amplification may explain the poor prognosis and therapy resistance of ERBB2 ‐amplified ILBC.
    Type of Medium: Online Resource
    ISSN: 2056-4538 , 2056-4538
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2814357-7
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  • 5
    In: Nature, Springer Science and Business Media LLC, Vol. 578, No. 7796 ( 2020-02-27), p. 615-620
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    RVK:
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 6
    In: EBioMedicine, Elsevier BV, Vol. 63 ( 2021-01), p. 103182-
    Type of Medium: Online Resource
    ISSN: 2352-3964
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2799017-5
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  • 7
    In: The Journal of Pathology: Clinical Research, Wiley, Vol. 7, No. 2 ( 2021-03), p. 135-143
    Abstract: Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID‐19) has spread globally. The causes of death in COVID‐19 are frequently compared to a seasonal influenza outbreak. Complete COVID‐19 autopsy studies were almost non‐existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID‐19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID‐19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the ‘Spanish’ influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID‐19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID‐19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID‐19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS‐related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events.
    Type of Medium: Online Resource
    ISSN: 2056-4538 , 2056-4538
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2814357-7
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  • 8
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 9 ( 2022-2-9)
    Abstract: Long-term sequelae of coronavirus disease 2019 (COVID-19), including the interaction between persisting viral-RNA and specific tissue involvement, pose a challenging issue. In this study, we addressed the chronological correlation (after first clinical diagnosis and postmortem) between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and organ involvement. Methods The presence of postmortem SARS-CoV-2 RNA from 35 complete COVID-19 autopsies was correlated with the time interval between the first diagnosis of COVID-19 and death and with its relationship to morphologic findings. Results Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be evident up to 40 days after the first diagnosis and can persist to 94 hours after death. Postmortem SARS-CoV-2 RNA was mostly positive in lungs (70%) and trachea (69%), but all investigated organs were positive with variable frequency. Late-stage tissue damage was evident up to 65 days after initial diagnosis in several organs. Positivity for SARS-CoV-2 RNA in pulmonary swabs correlated with diffuse alveolar damage ( p = 0.0009). No correlation between positive swabs and other morphologic findings was present. Cerebral ( p = 0.0003) and systemic hemorrhages ( p = 0.009), cardiac thrombi ( p = 0.04), and ischemic events ( p = 0.03) were more frequent in the first wave, whereas bacterial pneumonia ( p = 0.03) was more prevalent in the second wave. No differences in biometric data, clinical comorbidities, and other autopsy findings were found. Conclusions Our data provide evidence not only of long-term postmortem persisting SARS-CoV-2 RNA but also of tissue damage several weeks after the first diagnosis of SARS-CoV-2 infection. Additional conditions, such as concomitant bacterial pulmonary superinfection, lung aspergillosis, thromboembolic phenomena, and hemorrhages can further worsen tissue damage.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2775999-4
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  • 9
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2023
    In:  Nature Methods Vol. 20, No. 9 ( 2023-09), p. 1310-1322
    In: Nature Methods, Springer Science and Business Media LLC, Vol. 20, No. 9 ( 2023-09), p. 1310-1322
    Abstract: Rapid, highly multiplexed, nondestructive imaging that spans the molecular to the supra-cellular scale would be a powerful tool for tissue analysis. However, the physical constraints of established imaging methods limit the simultaneous improvement of these parameters. Whole-organism to atomic-level imaging is possible with tissue-penetrant, picometer-wavelength X-rays. To enable highly multiplexed X-ray imaging, we developed multielement Z-tag X-ray fluorescence (MEZ-XRF) that can operate at kHz speeds when combined with signal amplification by exchange reaction (SABER)-amplified Z-tag reagents. We demonstrated parallel imaging of 20 Z-tag or SABER Z-tag reagents at subcellular resolution in cell lines and multiple human tissues. We benchmarked MEZ-XRF against imaging mass cytometry and demonstrated the nondestructive multiscale repeat imaging capabilities of MEZ-XRF with rapid tissue overview scans, followed by slower, more sensitive imaging of low-abundance markers such as immune checkpoint proteins. The unique multiscale, nondestructive nature of MEZ-XRF, combined with SABER Z-tags for high sensitivity or enhanced speed, enables highly multiplexed bioimaging across biological scales.
    Type of Medium: Online Resource
    ISSN: 1548-7091 , 1548-7105
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2163081-1
    SSG: 12
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  • 10
    In: Respiration, S. Karger AG, Vol. 101, No. 2 ( 2022), p. 155-165
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO­VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22–89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ 〈 sup 〉 2 〈 /sup 〉 and Mann-Whitney U tests. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Severe pulmonary endotheliitis ( 〈 i 〉 p 〈 /i 〉 = 0.031, 〈 i 〉 p 〈 /i 〉 = 0.029) and multi-organ involvement ( 〈 i 〉 p 〈 /i 〉 = 0.026, 〈 i 〉 p 〈 /i 〉 = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO­VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.
    Type of Medium: Online Resource
    ISSN: 0025-7931 , 1423-0356
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2022
    detail.hit.zdb_id: 1464419-8
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