Publications by authors named "Yuchen Han"

43 Publications

Challenging of frozen diagnoses of small sclerosing pneumocytoma.

J Clin Pathol 2021 Mar 29. Epub 2021 Mar 29.

Pathology Department, Shanghai Jiao Tong University Affiliated Chest Hospital, Shanghai, China.

Aims: An increasing number of small pulmonary nodules are being screened by CT, and an intraoperative diagnosis is necessary for preventing excessive treatment. However, there is limited literature on the frozen diagnosis of small sclerosing pneumocytomas (SPs). In particular, tumours smaller than 1 cm are challenging for pathologists performing intraoperative frozen diagnosis.

Methods: In total, 230 cases of SP were surgically resected between January 2015 and March 2019 at Shanghai Chest Hospital, and of them, 76 cases were smaller than 1 cm. The histology and clinical information of these 76 cases (33.0%, 76/230) were reviewed retrospectively, 54 cases of which were diagnosed intraoperatively, and the pitfalls were summarised. All diagnoses were confirmed on permanent sections and immunohistochemical sections.

Results: Histologically, 78.9% (60/76) of the small SP was dominated by one growth pattern, and solid and papillary growth pattern were the most commonly misdiagnosed circumstances. The rate of intraoperative misdiagnosis of these SP smaller than 1 cm was 11.1% (6/54).

Conclusions: The main reason for misdiagnosis was failure to recognise the dual cell populations and the cellular atypia. Diagnostic clues include the gross morphology, the presence of dual-cell populations and a hypercellular papillary core, foam cell accumulation in glandular spaces and haemorrhage and haemosiderin on the periphery. In spite of awareness of pitfalls some cases may still be essentially impossible to diagnose on frozen section.
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http://dx.doi.org/10.1136/jclinpath-2020-206729DOI Listing
March 2021

Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population.

J Pathol Clin Res 2021 Mar 26. Epub 2021 Mar 26.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China.

The molecular profile of neurotrophic tyrosine kinase receptor (NTRK) gene fusions in lung adenocarcinoma (LUAD) is not fully understood. Next-generation sequencing (NGS) and pan-tyrosine kinase receptor (TRK) immunohistochemistry (IHC) are powerful tools for NTRK fusion detection. In this study, a total of 4,619 LUAD formalin-fixed, paraffin-embedded tissues were collected from patients who underwent biopsy or resection at the Shanghai Chest Hospital during 2017-2019. All specimens were screened for NTRK1 rearrangements using DNA-based NGS. Thereafter, the cases with NTRK1 rearrangements and cases negative for common driver mutations were analyzed for NTRK1/2/3 fusions using total nucleic acid (TNA)-based NGS and pan-TRK IHC. Overall, four NTRK1/2 fusion events were identified, representing 0.087% of the original sample set. At the DNA level, seven NTRK1 rearrangements were identified, while only two TPM3-NTRK1 fusions were confirmed on TNA-based NGS as functional. In addition, two NTRK2 fusions (SQSTM1-NTRK2 and KIF5B-NTRK2) were identified by TNA-based NGS in 350 'pan-negative' cases. Two patients harboring NTRK1/2 fusions were diagnosed with invasive adenocarcinoma, while the other two were diagnosed with adenocarcinoma in situ and minimally invasive adenocarcinoma. All four samples with NTRK fusions were positive for the expression of pan-TRK. The two samples with NTRK2 fusions showed cytoplasmic staining alone, while the other two samples with NTRK1 fusions exhibited both cytoplasmic and membranous staining. In summary, functional NTRK fusions are found in early-stage LUAD; however, they are extremely rare. According to this study's results, they are independent oncogenic drivers, mutually exclusive with other driver mutations. We demonstrated that NTRK rearrangement analysis using a DNA-based approach should be verified with an RNA-based assay.
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http://dx.doi.org/10.1002/cjp2.208DOI Listing
March 2021

Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC.

J Thorac Oncol 2021 04 29;16(4):643-652. Epub 2021 Jan 29.

Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China. Electronic address:

Introduction: Although the interaction between tumor immune microenvironment and angiogenesis has been well established, evidence supporting the chemo-free combination of immune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors in treatment-naive patients with advanced NSCLC is insufficient. This report provides the efficacy and safety of sintilimab combined with anlotinib as first-line therapy for advanced NSCLC from a phase 1b trial (NCT03628521).

Methods: Eligible patients who were treatment-naive and had unresectable stage IIIB/C or IV NSCLC without EGFR/ALK/ROS1 mutations received sintilimab (200 mg, day 1) and anlotinib (12 mg, day 1-14) every 3 weeks till disease progression or unacceptable toxicity. Baseline programmed death-ligand 1 expression and tumor mutation burden status was assessed in all patients. The primary end points were objective response rate and safety.

Results: A total of 22 patients received sintilimab and anlotinib. Median follow-up was 15.8 months (range: 8.3-19.3). Sixteen patients achieved confirmed partial response with an objective response rate of 72.7% (95% confidence interval [CI]: 49.8%-89.3%) and disease control rate of 100% (95% CI: 84.6%-100%). Median progression-free survival was 15 months (95% CI: 8.3 m, not reached), and the 12-month progression-free survival rate was 71.4% (95% CI: 47.2%-86.0%). The incidence rate of grade 3 or higher treatment-related adverse events was 54.5%, and grade 3 hypertension was predominant (two of 22, 9.1%). No grade 4 treatment-related adverse events were observed, and one case of grade 5 immune-related pneumonitis occurred.

Conclusions: To the best of our knowledge, this is the first study that assessed an anti-programmed cell death protein 1 antibody combined with a multitarget antiangiogenic tyrosine kinase inhibitor in the frontline setting for patients with NSCLC. In view of its encouraging efficacy, durability, and safety profile, sintilimab plus anlotinib represents a novel chemotherapy-free regimen in this patient population.
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http://dx.doi.org/10.1016/j.jtho.2020.11.026DOI Listing
April 2021

Morphological, immunohistochemical, and genetic analyses of bronchiolar adenoma and its putative variants.

J Pathol Clin Res 2021 May 5;7(3):287-300. Epub 2021 Jan 5.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China.

We collected 26 cases of bronchiolar adenoma (BA) and its variants, and performed a comprehensive characterization using a combination of morphological, immunohistochemical, and genetic assessments. Of these 26, 13 were classic bilayered cases, including 10 proximal and 3 distal-type BAs. Of note, we also identified 13 cases that lacked a continuous basal cell layer. In five cases, the adenomas were partially classic bilayered, leaving a single layer of columnar or cuboidal epithelial cells in some areas of the lesion (BA with monolayered cell lesions). In the other eight cases, the glandular or papillary structures were entirely composed of monolayered columnar or cuboidal epithelial cells, which were morphologically identical to the luminal epithelial cells of classic BA (monolayered BA-like lesions). Immunohistochemical analysis revealed thyroid transcription factor 1 expression by ciliated columnar epithelial cells, basal cells, and nonciliated columnar and cuboidal epithelial cells. Basal cells also expressed p40 and p63. Twenty-five cases underwent next-generation sequencing using a 422-cancer-gene panel (GeneseeqPrime). Oncogenic driver mutations were detected in 23 cases, including 13 (52%) with EGFR mutations, 4 (16%) with KRAS G12D/V mutations, 3 (12%) with BRAF V600E mutations, 2 (8%) with ERBB2 exon 20 insertions, and 1 (4%) with a RET fusion. EGFR exon 20 insertions were present in 100% of BAs with monolayered cell lesions, 37.5% of monolayered BA-like lesions, and 8% of classic BA (Fisher's exact test, p = 0.002, false discovery rate = 0.014). Collectively, our study revealed a gradual morphological transition between BA and its variants. The genetic composition of BAs with monolayered structures differed significantly from those of classic BAs or lung adenocarcinoma.
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http://dx.doi.org/10.1002/cjp2.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072999PMC
May 2021

Comprehensive Molecular Characterizations of Chinese Patients With Different Subtypes of Lung Squamous Cell Carcinoma.

Front Oncol 2020 10;10:607130. Epub 2020 Dec 10.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: This study aims to profile integrative genomic spectra of Chinese patients with different subtypes of lung squamous cell carcinoma (LUSC) and explore potential molecular prognosis factors.

Methods: We retrospectively identified 204 surgically resected LUSC patients in Shanghai Chest Hospital who underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer-related genes from September 2017 to January 2019. NGS was used to profile comprehensive molecular characterizations.

Results: Of 204 cases, 114 (55.9%) were keratinizing squamous cell carcinoma (KSCC), 77 (37.7%) were non-keratinizing squamous cell carcinoma (NKSCC), 13 (6.4%) were basaloid squamous cell carcinoma (BSCC), respectively. All subtypes presented similarly high proportions of mutations, including TP53, CDKN2A, and NOTCH1. A comparable prevalence of FGFR1 amplifications was identified between KSCC and NKSCC (11.4 26.9%, p = 0.007). Compared with NKSCC, IGF1R amplifications were more frequent in BSCC (0 15.4%, p = 0.019). We found cases with TP53 alterations had less EGFR alterations in KSCC (P = 0.013, OR = 0.158). Compared with TCGA cohorts, our Chinese cohorts exhibited statistic differences in both somatic mutations and signaling pathways. We found that STK 11 alterations and TOP2A alterations were significantly associated with higher risk of recurrence in patients with LUSC.

Conclusions: Significant differences exist among three subtypes of LUSC in molecular characterizations.
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http://dx.doi.org/10.3389/fonc.2020.607130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758445PMC
December 2020

Event- and time-based prospective memory in hemodialysis patients.

Ren Fail 2020 Nov;42(1):1135-1141

Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.

Objective: The present study investigated whether hemodialysis (HD) patients exhibit future memory impairment (PM; the capability of remembering to perform expected future actions) and exploring relevant factors of PM task performance.

Methods: Sixty HD patients and 60 healthy controls matched by age are enrolled in the Mini-Mental State Examination (MMSE), Finger Span Test (DST), Oral Fluency Test (VFT), Ray Auditory Oral Learning Test (RAVLT), Received Stroop Color Word Interference Test (SCWT), and event-based PM (EBPM) and time-based PM (TBPM).

Results: There were no significant difference between the patients and controls in the DST-Forward digit span (9.00 ± 1.25 versus 8.97 ± 1.33,  = 0.96), the DST-Backward digit span (5.23 ± 1.98 versus. 4.60 ± 1.65,  = 0.11), the RAVLT of delayed recall (7.28 ± 2.36 versus 6.87 ± 3.33,  = 0.09) and the VFT for animals (16.70 ± 3.50 versus 17.68 ± 5.45,  = 0.56). By comparison, patients had a much worse performance than controls on the MMSE (29.10 ± 0.84 versus 28.33 ± 0.77,  < 0.001), the RAVLT of total recall (44.47 ± 5.82 versus 40.03 ± 10.46,  < 0.001) and delayed recognition (6.93 ± 1.49 versus 5.4 ± 1.33,  < 0.001), the SCWT reaction time in reading (6.47 ± 1.05 versus 7.47 ± 1.86,  < 0.001), color naming (9.07 ± 1.29 versus 11.43 ± 2.34,  < 0.001), interference (8.78 ± 1.92 versus 10.22 ± 2.91,  < 0.001) and inhibition/switching (14.53 ± 2.90 versus 19.85 ± 4.69,  < 0.001), the VFT for fruit (17.47 ± 3.18 versus 15.92 ± 4.56,  < 0.001), the EBPM task (7.85 ± 0.40 versus 7.08 ± 1.43,  = 0.01), and the TBPM task (3.30 ± 1.31 versus 2.26 ± 1.82,  < 0.001).

Conclusions: Our results suggest that EBPM and TBPM are impaired in HD patients and that PM may be applied to help evaluate cognitive dysfunction in HD patients.
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http://dx.doi.org/10.1080/0886022X.2020.1835673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671658PMC
November 2020

PWP1 Promotes the Malignant Phenotypes of Lung Cancer Cells by Interacting with DVL2 and Merlin.

Onco Targets Ther 2020 8;13:10025-10037. Epub 2020 Oct 8.

Department of Pathology, College of Basic Medical Science, and First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.

Purpose: The significance of periodic tryptophan protein 1 (PWP1) expression in human cancer and its molecular mechanism of action have not been reported so far.

Materials And Methods: Immunohistochemistry was performed to analyze the expression of PWP1 in non-small cell lung cancer (NSCLC) tissues and statistical analysis was applied to analyze the relationship between PWP1 expression and the clinicopathological factors. The effects of PWP1 on NSCLC proliferation and invasion were determined by colony formation, transwell and MTT assays. Western blot analysis (WB), dual-luciferase reporter gene assays and immunofluorescence staining were performed to demonstrate whether PWP1 stimulates Wnt pathway and inhibits Hippo pathway. Co-immunoprecipitation (Co-ip) assays were used to confirm the potential role of PWP1 in Wnt and Hippo signaling pathways.

Results: PWP1 expression in NSCLC was higher than that in normal bronchial epithelium and normal submucosal glands. In addition, PWP1 expression had a positive correlation with poor differentiation, high pathological tumor-node-metastasis (TNM) stage, and lymph node metastasis. Kaplan-Meier database demonstrated that the overall survival time of patients with high PWP1 expression was significantly shorter than that of patients with low PWP1 expression. Mechanistically, we found that PWP1 could interact with DVL2 to upregulate β-catenin (thereby activating the Wnt pathway), whereas PWP1 could interact with Merlin (NF2) to downregulate p-MST1 (thereby inhibiting the Hippo signaling pathway). The effects of PWP1 on promoting the Wnt pathway or inhibiting the Hippo pathway were offset in DVL2- or Merlin-knockdown cells transiently overexpressing PWP1.

Conclusion: PWP1 expression in NSCLC was correlated with poor prognosis. PWP1 enhanced the activity of the Wnt pathway by interacting with DVL2, whereas PWP1 inhibited the activity of the Hippo pathway by interacting with Merlin. Together, these two effects promoted the detrimental biological behaviors of NSCLC cells.
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http://dx.doi.org/10.2147/OTT.S263815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553635PMC
October 2020

Molecular and clinicopathological characteristics of ROS1-rearranged non-small-cell lung cancers identified by next-generation sequencing.

Mol Oncol 2020 11 14;14(11):2787-2795. Epub 2020 Sep 14.

Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China.

ROS1 gene rearrangements have been reported in diverse cancer types including non-small-cell lung cancer (NSCLC), and with a notably higher prevalence in lung adenocarcinoma. The tyrosine kinase inhibitors, crizotinib, lorlatinib, and entrectinib, have demonstrated favorable efficacy in treating ROS1-rearranged NSCLCs. Herein, we retrospectively reviewed 17 158 NSCLC patients whose tumor specimen and/or circulating cell-free DNA underwent comprehensive genomic profiling. A total of 258 unique patients were identified with ROS1 rearrangements, representing an overall prevalence of approximately 1.5% of ROS1 fusions in newly diagnosed and relapsed NSCLC patients. CD74 (38%) was the most common fusion partner of ROS1, followed by EZR (13%), SDC4 (13%), SLC34A2 (10%), and other recurrent fusion partners with lower frequencies, including TPM3, MYH9, and CCDC6. Variant breakpoints occurred in ROS1 introns 33 (37%), 31 (25%), 32 (17%), and 34 (11%) with no obvious hotspots. CD74 (63%) and EZR (50%) were more frequently fused to ROS1 intron 33 than other introns, while ROS1 intron 31 was most frequently fused with SDC4 (79%) and SLC34A2 (81%). Crizotinib progression-free survival (PFS) was not significantly different between fusion variants involving breakpoints in different ROS1 introns, nor was there a significant difference in PFS between CD74-ROS1 and non-CD74-ROS1 groups of patients. Furthermore, TP53 was most frequently mutated in patients who progressed on crizotinib, and TP53 mutations were significantly associated with shorter crizotinib PFS. ROS1 mutations, including G2032R, were observed in approximately 33% of post-crizotinib samples. Collectively, we report the prevalence of ROS1 fusions in a large-scale NSCLC population and the efficacy of crizotinib in treating patients with ROS1-rearranged NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607175PMC
November 2020

The combination of ATA classification and FNA results can improve the diagnostic efficiency of malignant thyroid nodules.

Endocr Connect 2020 Sep;9(9):903-911

Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Purpose: To determine the diagnostic efficiency of the ATA classification and ultrasound-guided fine-needle aspiration (FNA) results in identifying the risk factors of malignancy, we analyzed the thyroid nodules of patients who underwent thyroidectomy and compared preoperative ATA classifications with FNA results.

Methods: We retrospectively analyzed 274 nodules of 196 patients who underwent ultrasonography, FNA and thyroidectomy. Histopathological findings of thyroid nodules were considered as the Au standard in the analysis of the diagnostic efficiency of the ATA classification and FNA results. Univariate analysis and binary multivariate logistic regression analysis were applied to identify the ultrasound features associated with malignancy.

Results: The overall malignancy rate of 274 nodules was 41.6%. The areas under the ROC curves (AUCs) for the ATA classification and FNA results were 0.88 and 0.878, respectively (P < 0.001). The sensitivity and specificity of the ATA classification were 86 and 86.9%, whereas those of FNA results were 68.5 and 91.4%, respectively. The specificity (98.7%) and sensitivity (94.3%) increased after the combined use of the ATA classification and FNA results. Taller-than-wide shape, microcalcifications, hypoechogenicity and irregular margins were independent risk factors for malignancy. Microcalcifications had the highest OR (7.58), and taller-than-wide shape had the highest specificity in BSRTC I, II, III and IV cytology.

Conclusion: The diagnostic efficiency of the ATA classification and FNA results in identifying malignant nodules was high, and the use of both criteria improved the diagnostic accuracy. Taller-than-wide shape, microcalcifications, hypoechogenicity and irregular margins were independent risk factors for malignancy.
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http://dx.doi.org/10.1530/EC-20-0303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583133PMC
September 2020

Study on Pyramidal Molybdenum Nanostructures Cold Cathode with Large-Current Properties Based on Self-Assembly Growth Method.

ACS Appl Mater Interfaces 2020 Aug 22;12(31):35354-35364. Epub 2020 Jul 22.

State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou 510275, P. R. China.

In order to develop a field emission cold cathode for power vacuum electronic device applications, it is important to realize the properties of large-current and high current density. This requires the design and preparation of cold cathode materials with good crystallization, suitable geometric structure, and good contact interface. In this study, we report a pyramidal molybdenum nanostructure with single crystalline nature, which was self-assembly grown by a thermal evaporation method. We also report the optimization of the nanostructure, successfully sharpening its top end and reducing the thickness of the intermediate layer between the structure and the substrate (from 31.4 to 3.1 nm). By this way, the pyramidal molybdenum nanostructure exhibits high conductivity of about 1.8 × 10 Ω cm. The cold cathode composed by these nanostructures shows a large-current field emission performance, with the largest emission current of 47.62 mA as well as the highest current density of 2.38 A cm, under a pulsed electric field as high as 28 V μm. The proposed pyramidal molybdenum nanostructures provide a candidate for the large-current cold cathode of the power electronic devices.
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http://dx.doi.org/10.1021/acsami.0c09345DOI Listing
August 2020

Metagenomics Meets Electrochemistry: Utilizing the Huge Catalytic Potential From the Uncultured Microbial Majority for Energy-Storage.

Front Bioeng Biotechnol 2020 4;8:567. Epub 2020 Jun 4.

Molecular Biology of Microbial Consortia, Biocenter Klein Flottbek, University of Hamburg, Hamburg, Germany.

Hydrogen can in the future serve as an advantageous carrier of renewable energy if its production via water electrolysis and utilization in fuel cells are realized with high energy efficiency and non-precious electrocatalysts. In an unprecedented novel combination of structured electrodes with hydrogen converting enzymes from the uncultured and thus largely inaccessible microbial majority (>99%) we address this challenge. The geometrically defined electrodes with large specific surface area allow for low overpotentials and high energy efficiencies to be achieved. Enzymatic hydrogen evolution electrocatalysts are used as alternatives to noble metals. The enzymes are harnessed from the environmental microbial DNA (metagenomes) of hydrothermal vents exhibiting dynamic hydrogen and oxygen concentrations and are recovered via a recently developed novel activity-based screening tool. The screen enables us to target currently unrecognized hydrogenase enzymes from metagenomes via direct expression in a surrogate host microorganism. This circumvents the need for cultivation of the source organisms, the primary bottleneck when harnessing enzymes from microbes. One hydrogen converting metagenome-derived enzyme exhibited high activity and unusually high stability when dispersed on a TiO-coated polyacrylonitrile fiber electrode. Our results highlight the tremendous potential of enzymes derived from uncultured microorganisms for applications in energy conversion and storage technologies.
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http://dx.doi.org/10.3389/fbioe.2020.00567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287016PMC
June 2020

An effective inflation treatment for frozen section diagnosis of small-sized lesions of the lung.

J Thorac Dis 2020 Apr;12(4):1488-1495

Department of Pathology, Shanghai Chest Hospital, Shanghai JiaoTong University, Shanghai 230000, China.

Background: The accuracy of intraoperative pathological diagnosis of small-sized pulmonary nodules including ground-glass opacity (GGO) is important for the surgeon to choose a suitable surgical procedure. Diagnosis of the small-sized lesions of the lung by frozen section (FS) is very difficult for the pathologist because of limited FS technology. Here we tested an effective inflation treatment for FS to improve the diagnostic accuracy of small-sized lung lesions.

Methods: The lung specimens were derived from 113 patients who underwent the surgery at Shanghai Chest Hospital in 2018-2019. The specimens were randomly divided into two groups-uninflated or inflated with diluted embedding medium (Tissue-Tek OCT; Sakura Finetek-USA, CA). The qualities of the FSs were compared with that of corresponding permanent paraffin sections. The FS diagnoses were compared with the final pathologic diagnoses of corresponding permanent sections.

Results: Our results showed that the quality of FS of lung tissue was excellent after inflation with diluted embedding medium (1:1). The total consistency between diagnosis of inflated FS and final pathological diagnosis was 85.7%. In control group, however, the consistency was only 70.2%. When the lesions were less than 1cm, the consistency between diagnosis of inflated FS and final pathological diagnosis was 90.3%, compared to 64.9% consistency in uninflated group (P=0.014, <0.05). When the lesions' computed tomography (CT) measurement threshold ≤-350 HU, the consistency between diagnosis of inflated FS and final pathological diagnosis was 88% compared to 73.2% consistency in uninflated group (P=0.071, >0.05). Accuracy, sensitivity and specificity were observed about 90% for adenocarcinoma (AIS), whereas it is drop to more than 80% for minimally invasive adenocarcinoma (MIA) in inflated FS.

Conclusions: Inflation with diluted embedding medium (1:1) could make lung tissue expand well during FS. By using this method, small-sized lesions (especially less than 1 cm) could be correctly diagnosed to enable adequate surgical procedure, and evaluation of which can be easily based on the intraoperative pathological diagnosis. The small lesions especially AIS could be readily identified on FS. Therefore, this method improves the diagnostic accuracy of FSs for small-sized lung lesions, and has important practical consequences for further therapy.
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http://dx.doi.org/10.21037/jtd.2020.02.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212135PMC
April 2020

Pyramid-Shaped Single-Crystalline Nanostructure of Molybdenum with Excellent Mechanical, Electrical, and Optical Properties.

ACS Appl Mater Interfaces 2020 May 6;12(21):24218-24230. Epub 2020 May 6.

State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.

Specific geometric morphology and improved crystalline properties are of great significance for the development of materials in micro-nano scale. However, for high-melting molybdenum (Mo), it is difficult to get high-quality structures exhibiting a single-crystalline nature and preconceived morphology simultaneously. In this paper, a pyramid-shaped single-crystalline Mo nanostructure was prepared through a thermal evaporation technique, as well as a series of experimental controls. Based on detailed characterizations, the growth mechanism was demonstrated to follow a sequential process that includes MoO decomposition and Mo deposition, single-crystalline islands formation, layered nucleation, and competitive growth. Furthermore, the product was measured to show excellent physical properties. The prepared nanostructures exhibited strong nano-indentation hardness, elastic modulus, and tensile strength in mechanical measurements, which are much higher than those of the Mo bulks. In the measurement of electronic characteristics, the individual structures indicated very good electrical transport properties, with a conductance of ∼0.16 S. The prepared film with an area of 0.02 cm showed large-current electron emission properties with a maximum current of 33.6 mA and a current density of 1.68 A cm. Optical properties of the structures were measured to show obvious electromagnetic field localization and enhancement, which enabled it to have good surface enhanced Raman scattering (SERS) activity as a substrate material. The corresponding structure-response relationships were further discussed. The reported physical properties profit from the basic features of the Mo nanostructures, including the micro-nano scale, the single-crystalline nature in each grain, as well as the pyramid-shaped top morphology. The findings may provide a potential material for the research and application of micro-nano electrons and photons.
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http://dx.doi.org/10.1021/acsami.0c02351DOI Listing
May 2020

Clinicopathologic features and genomic analysis of pulmonary blastomatoid carcinosarcoma.

BMC Cancer 2020 Mar 24;20(1):248. Epub 2020 Mar 24.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241 West Huaihai Road, Shanghai, 200030, China.

Background: This study was designed to investigate the clinicopathologic features of pulmonary blastomatoid carcinosarcoma and explore the genomic profiles of epithelial and mesenchymal components in this tumor.

Methods: Three cases of pulmonary blastomatoid carcinosarcoma were enrolled in this study. Clinicopathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were microdissected to investigate the genomic profiles by performing capture-based targeted next generation sequencing.

Results: The epithelial components in patient one consisted of low-grade and high-grade fetal lung adenocarcinoma. Low-grade epithelial cells showed nuclear expression of β-catenin and missense mutation of CTNNB1. The epithelial components in another two patients consisted of high-grade fetal lung adenocarcinoma/enteric adenocarcinoma. The epithelial cells showed membrane staining of β-catenin and harbored no mutation of CTNNB1. The mesenchymal components in all three tumors were composed of primitive round/spindle cells without definite differentiation and showed cytoplasmic dot positive of β-catenin and no corresponding mutation. Within a tumor, both components exhibited relatively comparable molecular profile. In patient one, 4 mutations: RB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial component had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient two, 12 mutations were shared. The epithelial component had BRCA2 mutation and the mesenchymal had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN and RICTOR. Patient three had 6 shared mutations. The epithelial component had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor.

Conclusions: Blastomatoid carcinosarcoma showed characteristic morphology and immunophenotype. Parallel detection of genetic abnormalities in epithelial and mesenchymal components could provide further evidence for tumor differentiation, molecular targeting and differential diagnosis.
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http://dx.doi.org/10.1186/s12885-020-06748-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092447PMC
March 2020

Molecular Profiling for Supernatants and Matched Cell Pellets of Pleural Effusions in Non-Small-Cell Lung Cancer.

J Mol Diagn 2020 04 7;22(4):513-522. Epub 2020 Feb 7.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China. Electronic address:

Pleural effusion (PE) is commonly observed in advanced lung cancer patients. Cell-free total nucleic acid (cfTNA) isolated from cancer patients' plasma has allowed noninvasive tumor genome analyses; however, there are limited studies of detection and characterization of cfTNA in PE. Herein, we included 47 advanced non-small-cell lung cancer patients with PE, who had lung cancer driver mutations tested on tumor tissue specimens either at diagnosis or during disease progression. The supernatant and cell pellet of each PE were evaluated for molecular profiles in parallel on an Ion Torrent next-generation sequencing platform. Somatic mutations were detected in 89.1% supernatant cfTNA, but in only 54.3% of cell pellets. The overall concordance rate between supernatants and formalin-fixed, paraffin-embedded cell pellets at the mutation level was 53.3%. By contrast, 41.7% and 5.0% of somatic alterations were detected in supernatants and cell pellets, respectively. Furthermore, joint analysis of supernatants and cell pellets from PE showed a high concordance (88.3%) of variant detection with their respective tumor tissue specimens. Low-frequency T790M mutations in three cases (0.29%, 0.41%, and 1.56%) were detected in supernatants but not in the matched cell pellets or tumor tissues. In conclusion, pleural effusion-derived cfTNA can effectively be used in clinical practice for molecular analysis by next-generation sequencing, even in cases where corresponding cell pellets or tumor tissues yield insufficient material.
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http://dx.doi.org/10.1016/j.jmoldx.2020.01.011DOI Listing
April 2020

Deciphering tissue-based proteome signatures revealed novel subtyping and prognostic markers for thymic epithelial tumors.

Mol Oncol 2020 04 6;14(4):721-741. Epub 2020 Feb 6.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, China.

Thymic epithelial tumors (TETs) belong to a group of tumors that rarely occur, but have unresolved mechanisms and heterogeneous clinical behaviors. Current care of TET patients demands biomarkers of high sensitivity and specificity for accurate histological classification and prognosis management. In this study, 134 fresh-frozen tissue samples (84 tumor, 40 tumor adjacent, and 10 normal thymus) were recruited to generate a quantitative and systematic view of proteomic landscape of TETs. Among them, 90 samples were analyzed by data-independent acquisition mass spectrometry (DIA-MS) leading to discovery of novel classifying molecules among different TET subtypes. The correlation between clinical outcome and the identified molecules was probed, and the prioritized proteins of interest were further validated on the remaining samples (n = 44) via parallel reaction monitoring (PRM) as well as immunohistochemical and confocal imaging analysis. In particular, two proteins, the cellular mRNA deadenylase CCR4 (carbon catabolite repressor 4)-NOT (negative on TATA) complex subunit 2/9 (CNOT2/9) and the serine hydroxymethyltransferase that catalyzes the reversible interconversions of serine and glycine (SHMT1), were found at dramatic low levels in the thymic epithelia of more malignant subtype, thymic squamous cell carcinoma (TSCC). Interestingly, the mRNA levels of these two genes were shown to be closely correlated with prognosis of the TET patients. These results extended the existing human tissue proteome atlas and allowed us to identify several new protein classifiers for TET subtyping. Newly identified subtyping and prognosis markers, CNOT2/9 and SHMT1, will expand current diagnostic arsenal in terms of higher specificity and prognostic insights for TET diagnosis and management.
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http://dx.doi.org/10.1002/1878-0261.12642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138395PMC
April 2020

Diaphragmatic dysfunction associates with dyspnoea, fatigue, and hiccup in haemodialysis patients: a cross-sectional study.

Sci Rep 2019 12 18;9(1):19382. Epub 2019 Dec 18.

Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China.

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p < 0.01) and thickening fraction (TF) (0.838 ± 0.618 vs. 1.127 ± 0.757; p < 0.01) compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing (3.686 ± 1.567 cm/s vs. 4.410 ± 1.720 cm/s, p < 0.01; 5.290 ± 2.048 cm vs. 7.232 ± 2.365 cm; p < 0.05). Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls (2.608 ± 1.630 vs. 4.628 ± 2.110 cm; p < 0.01). After multivariate adjustment, diaphragmatic excursion during deep breathing was associated with haemoglobin level (regression coefficient = 0.022; p < 0.01). We also found that the incidence of dyspnoea and hiccup and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients.
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http://dx.doi.org/10.1038/s41598-019-56035-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920450PMC
December 2019

Fbxw7 and Skp2 Regulate Stem Cell Switch between Quiescence and Mitotic Division in Lung Adenocarcinoma.

Biomed Res Int 2019 25;2019:9648269. Epub 2019 Aug 25.

Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.

Background/aims: The molecular mechanism of dormancy initiation of cancer stem cells (CSCs) is not clear. This study was to explore the molecular mechanism by which CSCs switch from mitotic division to quiescence.

Methods: MTT assays, flow cytometry, Western blotting, qRT-PCR, and immunofluorescence staining were used to test cell viability, cell cycle and expression of -box and WD repeat domain-containing 7 (Fbxw7), -myc, S phase kinase associated protein-2 (Skp2), cyclin-dependent kinase inhibitor 1B (p27), octamer-binding transcription factor 3/4 (Oct3/4), and catenin gene in 5-fluorouracil (5-FU)-treated A549 cells. Lung adenocarcinoma xenograft models were employed to detect the effects of Fbxw7 on tumor growth.

Results: 5-FU inhibited the proliferation of A549 cells, with a median inhibitory concentration (IC50) of 200 g/ml after 24 h treatment. 5-FU treatment increased the expressions of Oct3/4, Fbxw7, and p27 and increased the number of A549 cells at G0/G1. 5-FU treatment triggered nuclear translocation of -catenin, decreased the expression levels of c-myc and Skp2, and decreased the number of A549 cells at S phase. Release from 5-FU decreased the expressions of Oct3/4, Fbxw7 and p27; decreased the percentage of cells in the G0/G1 phase; increased the expressions of Skp2 and c-myc; and increased the proportion of cells in S phase. 5-FU treatment led to high expressions of Oct3/4, c-myc, and p27, with low expressions of Fbxw7 and Skp2. Knockdown of Fbxw7 augmented the expression of c-myc and decreased the proportion of A549 cells in Go/G1 phase. Skp2 siRNA increased the expression of p27 and the percentage of G0/G1 phase cells and reduced the proportion of S phase cells. Fbxw7 overexpression inhibited tumor growth in mouse lung adenocarcinoma xenograft models. When Fbxw7 expression was low, Skp2 expression was higher in lung adenocarcinoma tissues and associated with the differentiation of lung adenocarcinoma.

Conclusion: 5-FU enriches the CSCs in lung adenocarcinoma cells increasing Fbxw7 and decreasing Skp2 expression, followed by downregulation of c-myc and upregulation of p27, which switches cells to quiescence.
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http://dx.doi.org/10.1155/2019/9648269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732578PMC
February 2020

Long-term efficacy of afatinib in a patient with squamous cell carcinoma of the lung and multiple ERBB family aberrations: afatinib in ERBB+ lung squamous cell carcinoma.

Anticancer Drugs 2019 09;30(8):873-878

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

In the phase 3 LUX-Lung 8 study, the ERBB family blocker, afatinib, significantly prolonged progression-free survival and overall survival relative to erlotinib in patients with relapsed/refractory squamous cell carcinoma of the lung. We describe the case of a 53-year-old Asian male enrolled in LUX-Lung 8 who experienced long-term benefit from afatinib following failure of platinum-based chemotherapy. The patient received afatinib, and remained progression-free for 14.7 months according to investigator review. Overall survival was 17.7 months. Tolerability-guided dose adjustments helped facilitate long-term afatinib use by mitigating drug-related adverse effects. Next-generation sequencing revealed that multiple genetic aberrations were present, including epidermal growth factor receptor copy number amplification, and mutations in ERBB4, ALK, RET, and BRCA2. These findings may help to explain the enhanced response to afatinib and highlight the importance of biomarker analysis in guiding treatment decisions in patients with squamous cell carcinoma of the lung.
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http://dx.doi.org/10.1097/CAD.0000000000000813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727938PMC
September 2019

Malignant perivascular epithelioid cell tumor of the lung synchronous with a primary adenocarcinoma: one case report and review of the literature.

BMC Cancer 2019 Mar 15;19(1):235. Epub 2019 Mar 15.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241 West Huaihai Road, Shanghai, 200030, China.

Background: Perivascular Epithelioid Cell Tumors (PEComa) is an extraordinarily rare mesenchymal neoplasm especially the malignant type originating from the lung. To date, only 8 cases of malignant or malignant potential pulmonary PEComa had been documented. Firm diagnostic criteria for malignant pulmonary PEComa need urgently to be established.

Case Presentation: We report a challenging case of malignant pulmonary PEComa combined with a primary adenocarcinoma in a 54-year-old man. The PEComa-like tumor showed strong Melan-A and weak transcription factor E3 (TFE3) protein expression but no TFE3 gene rearrangement. The carcinoma-like nodule was recognized as a poorly differentiated primary lung adenocarcinoma.

Discussion And Conclusions: Our case report was the first case of malignant pulmonary PEComa synchronous with a primary adenocarcinoma and studied the dilemma of diagnosing benign versus malignant criteria for this uncommon tumor.
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http://dx.doi.org/10.1186/s12885-019-5383-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419825PMC
March 2019

Clinicopathological Features of ALK Expression in 9889 Cases of Non-small-Cell Lung Cancer and Genomic Rearrangements Identified by Capture-Based Next-Generation Sequencing: A Chinese Retrospective Analysis.

Mol Diagn Ther 2019 06;23(3):395-405

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241, West Huai Hai Road, Xv Hui District, Shanghai, 200030, China.

Background: The clinicopathological features and genomic rearrangements of anaplastic lymphoma kinase (ALK) fusion cases have not been fully identified.

Objective: Our objective was to explore the status of ALK in non-small-cell lung cancer (NSCLC) specimens, to explore the relationships between ALK status and clinicopathological features and to identify genomic rearrangements via capture-based next-generation sequencing (NGS).

Methods: We tested 9889 NSCLC specimens for ALK status using the Ventana anti-ALK (D5F3) antibody. Clinicopathological features were analyzed and genomic rearrangements identified using capture-based NGS in 76 ALK-positive cases.

Results: In total, 485 specimens (4.90%) tested positive for ALK. The positivity rate was higher for adenocarcinoma samples than for non-adenocarcinoma samples (6.03 vs. 1.47%; p < 0.001) and for biopsies/cell blocks than for surgical specimens (7.00 vs. 4.16%; p < 0.001). Patient age, patient sex, specimen type, specimen histotype, and patient smoking history were all significantly correlated with ALK status. Genomic rearrangements were detected in 98.68% (75/76) of the ALK-positive samples; 89.33% (67/75) carried the canonical EML4-ALK, and the remaining samples carried only noncanonical ALK rearrangements. Four of these noncanonical ALK fusion samples were identified as carrying EML4-ALK transcripts at the RNA level. A novel fusion variant, SRD5A2-ALK, was revealed.

Conclusions: Younger patients with NSCLC, especially those aged < 30 years, were more likely to test positive for ALK. Positive ALK test results were more common in patients with invasive mucinous adenocarcinoma and solid-predominant invasive adenocarcinoma than in patients with other histotypes. Samples that carried only noncanonical ALK rearrangements may also have carried the canonical EML4-ALK, which was not detected by capture-based NGS. EML4-ALK transcripts might result from rare splicing mechanisms without genomic rearrangements.
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http://dx.doi.org/10.1007/s40291-019-00389-yDOI Listing
June 2019

Differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal carcinoma with the assistance of next-generation sequencing and immunohistochemistry.

J Cancer Res Clin Oncol 2019 Jan 10;145(1):269-279. Epub 2018 Nov 10.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.

Purpose: Pulmonary enteric adenocarcinoma (PEAC), defined as tumors with an enteric component exceeding 50% and a histological morphology similar to colorectal cancer (CRC) and metastatic colorectal carcinoma (MCC), is an extremely rare primary lung adenocarcinoma, which was recently recognized by World Health Organization (WHO). Adenocarcinomas with intestinal differentiation have also been described in other anatomic sites, including paranasal sinuses, extrahepatic biliary tree, uterine and cervix, ovary. The morphologic spectrum and immunohistochemical profiles of PEAC overlap with those of colonic adenocarcinomas, the diagnosis of PEAC remains challenging. Currently, colonoscopy has to be performed to confirm the diagnosis, resulting in low compliance due to its invasiveness. Due to the rareness of PEAC, its molecular signature has not been comprehensively examined.

Methods: In this study, we investigated the molecular signatures associated with PEAC and its histological counterparts, CRC and MCC using capture-based targeted sequencing.

Results: We revealed that 12/13 (92.31%) PEAC patients harbored mutations in well-established driver genes for non-small cell lung cancer and none of them had mutations unique to CRC. Furthermore, 13/15 (86.7%) of MCC harbored mutations that are frequently seen in CRC.

Conclusion: Collectively, our study showed that PEAC, exhibiting a similar mutational profile with NSCLC, showed a distinctive signature from CRC and MCC. Furthermore, we derived a classification model, intergrading both IHC markers and genetic signature, to accurately diagnose PEAC.
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http://dx.doi.org/10.1007/s00432-018-2788-0DOI Listing
January 2019

Solitary pulmonary capillary hemangioma: Clinicopathologic and radiologic characteristics of nine surgically resected cases.

Pathol Res Pract 2018 Nov 20;214(11):1885-1891. Epub 2018 Sep 20.

Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address:

Background: Solitary pulmonary capillary hemangioma (SPCH) is an extraordinarily rare capillary derived mesenchymal neoplasm. Although routine morphology and immunohistochemistry are adequate for the diagnosis of classical SPCH in surgical specimens, true gross appearance identification of most tumor themselves and diagnosis for some exceptional cases are still very difficult. Furthermore, preoperative imaging and frozen diagnosis remain a challenge.

Methods: We reported nine original cases of solitary pulmonary capillary hemangioma and summarized the clinical characteristics of twenty-one reported lesions. Imaging materials were reviewed by the image experts of our hospital. Quick hematoxylin-eosin stained intraoperative frozen sections and routine histological diagnosis were re-confirmed by 3 specialist pathologists with at least 10 years of diagnostic experience in our department. Immunohistochemistry analysis was performed on formalin fixed archival tissue. The surgical methods, following up information and prognosis were retrospectively analyzed.

Results: In imaging, three tumors showed solid nodules, three cases displayed mix ground glass nodules, two nodules were pure ground glass density, and one case was a cystic-solid mass. Macroscopically, solitary pulmonary capillary hemangiomas were ill-defined soft hemorrhagic lesion with pale yellow or dark brownish cut surface. Two cases had a clear boundary and seven lesions were poorly demarcated. Typical morphological features were densely proliferating thin-walled capillaries composing of single layer of flatten or cuboidal endothelial cells within the thickened alveolar septa. One case was mistaken for a histiocytogenic lesion during freezing. The cystic-solid lesion showed a hyperplasia capillary network along the submucosal interstitium of bronchioles. Immunohistochemically, tumor endothelial cells were positive for ERG, Fli-1, CD31, CD34 and Vimentin and negative for CK, α-SMA, TTF-1, HMB45, S-100 and CD68. Lobectomy was performed on seven cases, wedge resection and segmentectomy were proceeded in two patients respectively. Follow up information showed no evidence of complication or recurrence.

Conclusions: Solitary pulmonary capillary hemangioma has special imaging and various histological features and must be distinguished from small benign lung lesions and preinvasive cancer. Although the prognosis of this tumor is good after surgical resection, the correct interpretation of the gross appearance and radiographic findings are still important. Choosing appropriate resection mode depends on accurate evaluation preoperative and intraoperative.
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http://dx.doi.org/10.1016/j.prp.2018.09.014DOI Listing
November 2018

Hydrothermal chimneys host habitat-specific microbial communities: analogues for studying the possible impact of mining seafloor massive sulfide deposits.

Sci Rep 2018 07 10;8(1):10386. Epub 2018 Jul 10.

Universität Hamburg, MIN-Fakultät, Biocenter Klein Flottbek, Molecular Biology of Microbial Consortia, Ohnhorststr. 18, 22609, Hamburg, Germany.

To assess the risk that mining of seafloor massive sulfides (SMS) from extinct hydrothermal vent environments has for changing the ecosystem irreversibly, we sampled SMS analogous habitats from the Kairei and the Pelagia vent fields along the Indian Ridge. In total 19.8 million 16S rRNA tags from 14 different sites were analyzed and the microbial communities were compared with each other and with publicly available data sets from other marine environments. The chimneys appear to provide habitats for microorganisms that are not found or only detectable in very low numbers in other marine habitats. The chimneys also host rare organisms and may function as a vital part of the ocean's seed bank. Many of the reads from active and inactive chimney samples were clustered into OTUs, with low or no resemblance to known species. Since we are unaware of the chemical reactions catalyzed by these unknown organisms, the impact of this diversity loss and bio-geo-coupling is hard to predict. Given that chimney structures can be considered SMS analogues, removal of sulfide deposits from the seafloor in the Kairei and Pelagia fields will most likely alter microbial compositions and affect element cycling in the benthic regions and probably beyond.
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http://dx.doi.org/10.1038/s41598-018-28613-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039533PMC
July 2018

Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis.

Oncotarget 2017 Dec 18;8(62):104813-104830. Epub 2017 Aug 18.

Departments of Pathology, School of Basic Medical Sciences, China Medical University, Liaoning, China.

We investigated the role of lamin B2 in non-small cell lung cancer (NSCLC). We detected higher lamin B2 expression in 20 NSCLC tumor tissues obtained from The Cancer Genome Atlas than in adjacent normal lung tissues. LMNB2-RNAi knockdown in A549 and H1299 NSCLC cells inhibited colony formation, cell proliferation and G1-S cell cycle progression while increasing apoptosis. LMNB2 overexpression had the opposite effects. Tumor xenograft experiments showed diminished tumor growth with LMNB2 knockdown H1299 cells than with controls. Yeast two-hybrid studies revealed minichromosome maintenance complex component 7 (MCM7) to be a binding partner of lamin B2, which was confirmed by co-immunoprecipitation and co-localization studies. Lamin B2 binding enhanced DNA binding and helicase activities of MCM7. Deletion analysis with MCM7-N, MCM7-M or MCM7-C mutant proteins showed that lamin B2 binds to the C-terminus of MCM7, and competes with the binding of the tumor suppressor retinoblastoma (RB) protein. Immunohistochemical analysis of 150 NSCLC patient samples revealed that both lamin B2 and MCM7 levels positively correlated with histological grade and tumor TNM stage. Moreover, high lamin B2 and MCM7 levels correlated with shorter overall survival of NSCLC patients. In sum, these results show that lamin B2 interaction with MCM7 promotes NSCLC progression.
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http://dx.doi.org/10.18632/oncotarget.20338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739603PMC
December 2017

RACK1 promotes lung cancer cell growth via an MCM7/RACK1/ Akt signaling complex.

Oncotarget 2017 Jun;8(25):40501-40513

Department of Pathology, School of Basic Medical Sciences, China Medical University, Shenyang 110000, China.

MCM7, a member of the miniature chromosome maintenance (MCM) protein family, is crucial for the initiation of DNA replication and proliferation in eukaryotic cells. In this report, we demonstrate that RACK1 regulates cell growth and cell cycle progression in human non-small-cell lung cancer by mediating MCM7 phosphorylation through an MCM7/RACK1/Akt signaling complex. RACK1 functions as a central scaffold that brings Akt into physical proximity with MCM7. Overexpression of RACK1 increases interactions between Akt and MCM7 and promotes Akt-dependent MCM7 phosphorylation, which in turn increases MCM7 binding to chromatin and MCM complex formation. Together, these changes promote DNA replication and cell proliferation. Our findings reveal a novel signaling pathway that regulates growth in non-small cell lung cancer.
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http://dx.doi.org/10.18632/oncotarget.17120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522230PMC
June 2017

Sulfide Consumption in Sulfurimonas denitrificans and Heterologous Expression of Its Three Sulfide-Quinone Reductase Homologs.

J Bacteriol 2016 Apr 31;198(8):1260-7. Epub 2016 Mar 31.

Molecular Biology of Microbial Consortia, University of Hamburg, Biocenter Klein Flottbek, Hamburg, Germany

Unlabelled: Sulfurimonas denitrificans is a sulfur-oxidizing epsilonproteobacterium. It has been reported to grow with sulfide and to harbor genes that encode sulfide-quinone reductases (SQRs) (catalyze sulfide oxidation). However, the actual sulfide concentrations at which S. denitrificans grows and whether its SQRs are functional remain enigmatic. Here, we illustrate the sulfide concentrations at which S. denitrificans exhibits good growth, namely, 0.18 mM to roughly 1.7 mM. Around 2.23 mM, sulfide appears to inhibit growth. S. denitrificans harbors three SQR homolog genes on its genome (Suden_2082 for type II SQR, Suden_1879 for type III SQR, and Suden_619 for type IV SQR). They are all transcribed in S. denitrificans. According to our experiments, they appear to be loosely bound to the membrane. Each individual S. denitrificans SQR was heterologously expressed in the Rhodobacter capsulatus SB1003 sqr deletion mutant, and all exhibited SQR activities individually. This suggests that all of these three genes encode functional SQRs. This study also provides the first experimental evidence of a functional bacterial type III SQR.

Importance: Although the epsilonproteobacterium Sulfurimonas denitrificans has been described as using many reduced sulfur compounds as electron donors, there is little knowledge about its growth with sulfide. In many bacteria, the sulfide-quinone reductase (SQR) is responsible for catalyzing sulfide oxidation. S. denitrificans has an array of different types of sqr genes on its genome and so do several other sulfur-oxidizing Epsilonproteobacteria. However, whether these SQRs are functional has remained unknown. Here, we shed light on sulfide metabolism in S. denitrificans. Our study provides the first experimental evidence of active epsilonproteobacterial SQRs and also gives the first report of a functional bacterial type III SQR.
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http://dx.doi.org/10.1128/JB.01021-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859588PMC
April 2016

The globally widespread genus Sulfurimonas: versatile energy metabolisms and adaptations to redox clines.

Front Microbiol 2015 16;6:989. Epub 2015 Sep 16.

Molecular Biology of Microbial Consortia, Biocenter Klein Flottbek, University of Hamburg Hamburg, Germany.

Sulfurimonas species are commonly isolated from sulfidic habitats and numerous 16S rRNA sequences related to Sulfurimonas species have been identified in chemically distinct environments, such as hydrothermal deep-sea vents, marine sediments, the ocean's water column, and terrestrial habitats. In some of these habitats, Sulfurimonas have been demonstrated to play an important role in chemoautotrophic processes. Sulfurimonas species can grow with a variety of electron donors and acceptors, which may contribute to their widespread distribution. Multiple copies of one type of enzyme (e.g., sulfide:quinone reductases and hydrogenases) may play a pivotal role in Sulfurimonas' flexibility to colonize disparate environments. Many of these genes appear to have been acquired through horizontal gene transfer which has promoted adaptations to the distinct habitats. Here we summarize Sulfurimonas' versatile energy metabolisms and link their physiological properties to their global distribution.
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http://dx.doi.org/10.3389/fmicb.2015.00989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584964PMC
October 2015

Epithelioid angiosarcoma at chest wall which needs to be carefully distinguished from malignant mesothelioma: report of a rare case.

Int J Clin Exp Pathol 2014 1;7(12):9056-60. Epub 2014 Dec 1.

Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences of China Medical University Shenyang 110001, China ; Institute of Pathology and Pathophysiology, China Medical University Shenyang 110001, China.

Angiosarcoma is a malignant soft tissue tumor the cells of which variably recapitulate the morphologic and functional features of normal endothelium. Most lesions are located in the deep muscles of the lower extremities followed by the arm, trunk and head and neck. Herein we present a case of epithelioid angiosarcoma which is a variant of angiosarcoma at chest wall in a 73-year-old female. Morphologically, the tumor cells are arranged predominantly in luminal structures which can be seen in both angiosarcoma and malignant mesothelioma. Most of the tumor cells are large rounded "epithelioid" cells with abundant eosinophilic cytoplasm which can be also seen in both tumors. The epithelioid of cytomorphology and the localization at chest wall of this case may remind of a diagnosis of malignant mesothelioma which should be carefully distinguished from epithelioid angiosarcoma from imaging and morphology. CT scanning of the patient shows a mass at her chest wall, the majority of which is around the rib but not inside the lung which indicates a tumor originates more likely from soft tissues of chest wall but not pleura. Immunohistochemical staining shows that the tumor cells are positive for cytokeratin, CD31, Vimentin and WT1, and negative for CEA, TTF-1, Calretinin, Mesothelial Cell (MC), CD56, CK19, and Hepatocyte. Thus this case is diagnosed as epithelioid angiosarcoma but not malignant mesothelioma. From this case we suggest that carefully reading and understanding of the imaging are a very important clue for appropriate diagnosis. A misdiagnosis may occur on the basis of misunderstanding of tumor localization and a consequent inappropriate immunohistochemical staining programme.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314036PMC
October 2015

The role of hydrogen for Sulfurimonas denitrificans' metabolism.

PLoS One 2014 29;9(8):e106218. Epub 2014 Aug 29.

Molecular Biology of Microbial Consortia, University of Hamburg, Biocenter Klein Flottbek, Hamburg, Germany.

Sulfurimonas denitrificans was originally isolated from coastal marine sediments. It can grow with thiosulfate and nitrate or sulfide and oxygen. Recently sequencing of its genome revealed that it encodes periplasmic and cytoplasmic [NiFe]-hydrogenases but the role of hydrogen for its metabolism has remained unknown. We show the first experimental evidence that S. denitrificans can indeed express a functional hydrogen uptake active hydrogenase and can grow on hydrogen. In fact, under the provided conditions it grew faster and denser on hydrogen than on thiosulfate alone and even grew with hydrogen in the absence of reduced sulfur compounds. In our experiments, at the time points tested, the hydrogen uptake activity appeared to be related to the periplasmic hydrogenase and not to the cytoplasmic hydrogenase. Our data suggest that under the provided conditions S. denitrificans can grow more efficiently with hydrogen than with thiosulfate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149538PMC
November 2015