The existence of an in situ phase of malignant mesothelioma has long been postulated but until recently has been impossible to prove. Here we describe ten patients with mesothelioma in situ, defined ...by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining, no evidence of tumor by imaging and/or by direct examination of the pleura/peritoneum, and no invasive mesothelioma developing for at least 1 year. Nine cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology; in two patients mesothelioma in situ was found incidentally in lung cancer resections. In addition to surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss, and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Methylthioadenosine phosphorylase showed partial loss in the surface mesothelium by immunohistochemistry in three cases. Invasive malignant mesothelioma developed in seven patients with time between biopsy and invasive disease from 12 to 92 (median 60) months. Invasive mesothelioma has not developed in the other three patients at 12, 57, and 120 months, but the latter patient, who has pleural plaques, still has repeated pleural effusions, probably representing a so-called "benign asbestos effusion." We conclude that mesothelioma in situ, as diagnosed using the criteria outlined above, is associated with a high risk of developing invasive mesothelioma, but typically over a relatively protracted time, so that curable interventions maybe possible.
Alzheimer’s disease (AD) is characterized by the accumulation and deposition of amyloid-beta (Aβ) peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the ...neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E (ApoE) proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-inflammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinflammation in AD.
Immunotherapy has vastly changed the treatment landscape for patients with advanced NSCLC. With high programmed death-ligand 1 (PD-L1) expression (tumor proportion score ≥50%), options include ...programmed cell death protein 1 or PD-L1 inhibitor with or without chemotherapy. A cut-point of greater than or equal to 50% defines PD-L1-high, but a more precise PD-L1 tumor proportion score may be an important predictor of outcomes.
We reviewed all patients with PD-L1-high NSCLC who received pembrolizumab from June 2019 to June 2021. Demographic, diagnosis, treatment, and outcomes data were collected retrospectively. The primary end point was a descriptive analysis of pembrolizumab prescribing patterns. Secondary end points included overall survival (OS) by treatment choice and absolute PD-L1 expression.
Overall, 132 patients received pembrolizumab; 124 (94%) as monotherapy, and 8 (6%) with chemotherapy. Baseline characteristics include the following: (1) median age 70 years (50-89); (2) 55% men; (3) 79% Eastern Cooperative Oncology Group performance status 0 to 1; and (4) 96% current or former smokers. There were 39% who have PD-L1 greater than or equal to 90% versus 61% with PD-L1 of 50% to 89%. The median OS in the overall population was 14.4 months. The median OS in the pembrolizumab monotherapy cohort and combination cohort were 13.6 months and 16.6 months, respectively (
= 0.67). Within the monotherapy cohort, the median OS was longer for PD-L1 greater than or equal to 90% (19.8 mo) versus PD-L1 50% to 89% (11.9 mo,
= 0.039). The 24-month OS was 27.8% among patients with PD-L1 50% to 89% and 47.4% among patients with PD-L1 greater than or equal to 90%.
Most patients with advanced PD-L1-high NSCLC received pembrolizumab monotherapy, among whom OS was strongly correlated with PD-L1 expression, with PD-L1 greater than or equal to 90% of patients experiencing substantially longer survival. PD-L1 expression level could be an important determinant in immunotherapy prescribing patterns and a predictor of success in advanced NSCLC.
Objective
COPA syndrome is a genetic disorder of retrograde cis‐Golgi vesicle transport that leads to upregulation of pro‐inflammatory cytokines (mainly IL‐1β and IL‐6) and the development of ...interstitial lung disease (ILD). The impact of COPA syndrome on post‐lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA‐ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy.
Methods
Multiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre‐ and post‐LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre‐ and post‐LTx were stimulated with PMA, LPS and anti‐CD3/CD28 antibodies. Post‐LTx endobronchial biopsies underwent microarray‐based gene expression analysis. Results were compared to non‐COPA LTx recipients and non‐LTx healthy controls.
Results
Multiplexed cytokine analysis showed rising type I/II IFNs, and IL‐6 in BAL post‐LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. In vitro stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL‐6 signalling pathways. Tocilizumab (IL‐6 receptor antibody) administration for 3 months (4 mg kg−1, monthly) effectively suppressed IL‐6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal.
Conclusion
Clinical effectiveness of IL‐6 receptor blockade was not observed. However, we identified IL‐6 upregulation associated with graft injury, effective IL‐6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL‐6 blockade in post‐LTx care that should be investigated further.
In this case report, we describe progressive allograft dysfunction following lung transplant for interstitial lung disease due to COPA syndrome. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy. We identified IL‐6 upregulation associated with graft injury, effective IL‐6 suppression with tocilizumab and evidence of beneficial effect of tocilizumab on molecular transcripts of rejection/injury. This mechanistic analysis suggests a role for IL‐6 blockade in post‐LTx care that should be investigated further.
MinE is required for the dynamic oscillation of Min proteins that restricts formation of the cytokinetic septum to the midpoint of the cell in gram negative bacteria. Critical for this oscillation is ...MinD-binding by MinE to stimulate MinD ATP hydrolysis, a function that had been assigned to the first ∼30 residues in MinE. Previous models based on the structure of an autonomously folded dimeric C-terminal fragment suggested that the N-terminal domain is freely accessible for interactions with MinD. We report here the solution NMR structure of the full-length MinE dimer from Neisseria gonorrhoeae, with two parts of the N-terminal domain forming an integral part of the dimerization interface. Unexpectedly, solvent accessibility is highly restricted for residues that were previously hypothesized to directly interact with MinD. To delineate the true MinD-binding region, in vitro assays for MinE-stimulated MinD activity were performed. The relative MinD-binding affinities obtained for full-length and N-terminal peptides from MinE demonstrated that residues that are buried in the dimeric interface nonetheless participate in direct interactions with MinD. According to results from NMR spin relaxation experiments, access to these buried residues may be facilitated by the presence of conformational exchange. We suggest that this concealment of MinD-binding residues by the MinE dimeric interface provides a mechanism for prevention of nonspecific interactions, particularly with the lipid membrane, to allow the free diffusion of MinE that is critical for Min protein oscillation.
Using an event study and data of publicly traded firms in Taiwan from 2005 through 2010, we examine the impact of corporate social responsibility (CSR) on mitigating the declines in shareholder value ...when firms are disclosed of negative events, i.e., the risk management effect. Our results show that firms engaging in CSR activity have less stock price declines when negative news are disclosed. We also find that this effect is significant for safetyrelated negative events, but not for market-competition and integrity-related events. Furthermore, the empirical results show that CSR has a long-term effect on reducing stock volatility., 本文探討企業善盡社會責任，對於股東價值是否具有風險管理的效果。即當企業被披露負面事件消息時，其平日所盡之社會責任，是否有助於減緩股價之下跌？本文採用台灣上市櫃公司資料，利用事件研究法進行實證分析。結果顯示：企業平日善盡社會責任所建立之形象，的確有助於企業在面臨不利報導時之股價的維持，意即「善有善報」。就負面消息類型而言，企業社會責任形象，對於與安全相關的負面消息，有較顯著的保護效果；對於與倫理道德相關的負面事件則不明顯；而對於與市場競爭有關的負面消息，企業之善盡社會責任形象，並無助於降低股價下跌的風險。此外，研究結果亦顯示企業之社會責任形象具有長期效應，有助於降低股價之波動性
Using an event study and data of publicly traded firms in Taiwan from 2005 through 2010, we examine the impact of corporate social responsibility (CSR) on mitigating the declines in shareholder value ...when firms are disclosed of negative events, i.e., the risk management effect. Our results show that firms engaging in CSR activity have less stock price declines when negative news are disclosed. We also find that this effect is significant for safetyrelated negative events, but not for market-competition and integrity-related events. Furthermore, the empirical results show that CSR has a long-term effect on reducing stock volatility.
When examined with polarized optical microscopy (POM), liquid crystals display interference colors and complex patterns that depend on the material’s microscopic orientation. That orientation can be ...manipulated by the application of external fields, a feature that provides the basis for applications in optical display and sensing technologies. The color patterns themselves have high information content. Traditionally, however, calculations of the optical appearance of liquid crystals have been performed by assuming that a single-wavelength light source is employed and reported on a monochromatic scale. In this work, the original Jones matrix method is extended to calculate the colored images that arise when a liquid crystal is exposed to a multiwavelength source. By accounting for the material properties, including the local orientation, the visible light spectrum, and the CIE (International Commission on Illumination) color matching functions, we demonstrate that the proposed approach produces colored POM images that are in quantitative agreement with experimental data. Results are presented for a variety of systems, including radial, bipolar, and cholesteric droplets, where results of simulations are compared with experimental images. The effects of the droplet size, topological defect structure, and droplet orientation are examined systematically. The technique introduced here generates images that can be directly compared to experiments, thereby facilitating machine learning efforts aimed at interpreting LC microscopy images and paving the way for the inverse design of materials capable of producing specific internal microstructures in response to external stimuli.
The aim of this study was to review the clinicopathologic characteristics of metastatic nonhematopoietic malignancies to the breast, in order to identify salient features for practicing pathologists ...that are useful in distinguishing metastatic lesions from primary breast neoplasms. A total of 238 cases were identified during the period from January 2005 to January 2015. Clinicopathologic features of these cases were retrospectively reviewed. Primary tumors included melanoma (99, 42%), serous carcinoma (35, 15%), neuroendocrine neoplasm (32, 13%), sarcoma (23, 10%), and adenocarcinoma from various organs (47, 20%), and 2 others. Most metastases were unilateral (223, 94%) and unifocal (206, 87%) and were detected radiographically (167, 70%). Concurrent ipsilateral axillary metastasis occurred in 33 (14%) patients. Among 238 cases, 41 had metastatic disease to the breast concurrently or preceding the primary cancer diagnosis. Notably, in 39 (16%) cases, breast metastasis was the first clinical presentation of disease, and 16 (41%) of these cases were initially misdiagnosed as breast primaries. In contrast, with a known history of nonmammary primary tumors, only 4 of 197 (2%) cases were misdiagnosed (p < 0.0001). Metastatic tumors share many overlapping features with breast primary carcinomas. However, cases with a well-circumscribed tumor, lack of in situ component, estrogen receptor/progesterone receptor negativity, and unusual morphologic features should raise the consideration of metastatic disease. While clinical history is paramount for correct diagnosis, metastasis to the breast as the first clinical presentation is not uncommon.
•Metastatic neoplasms to the breast are rare, but are often misdiagnosed as primary breast carcinomas.•Metastatic neoplasms to the breast can precede the primary cancer diagnosis and mimic primary breast carcinoma.•Prior cancer history, morphologic features, and a panel of tissue specific markers aid in establishing the correct diagnosis.
Alzheimer’s disease (AD) is the most common form of dementia. Pathologically, it is characterized by degeneration of neurons and synapses, the deposition of extracellular plaques consisting of ...aggregated amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein. Recently, the spotlights have been centered on two characteristics of AD, neuroinflammation and insulin resistance. Because both of these pathways play roles in synaptic dysfunction and neurodegeneration, they become potential targets for therapeutic intervention that could impede the progression of the disease. Here, we present an overview of the traditional amyloid hypothesis, as well as emerging data on both inflammatory and impaired insulin signaling pathways in AD. It becomes evident that more than one concurrent treatment can be synergistic and various combinations should be discussed as a potential therapeutic strategy to correct the anomalies in AD. Insulin resistance, Aβ/tau pathologies, neuroinflammation, and dysregulation of central nervous system homeostasis are intertwined processes that together create the complex pathology of AD and should be considered as a whole picture.
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