Thymic epithelial neoplasms are rare tumors that are difficult to diagnose and treat. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed by various malignancies and are ...considered a prognostic factor and immunotherapeutic target. We examined the expression of both antibodies in 100 thymic epithelial neoplasms to assess their use as a biomarker and to correlate their expression with clinicopathological parameters. Whole-tissue sections of 74 thymomas and 26 thymic carcinomas were examined. Expression of PD-1 and PD-L1 was evaluated by immunohistochemistry and scored by the percentage of positive T-cells or tumor cells, respectively. Cases with strong membranous reactivity of the antibody in ≥5% of T-cells (PD-1) or tumor cells (PD-L1), respectively, were considered positive. Expression of PD-1 was detected in 52/100 cases (52%) including 6/26 thymic carcinomas (23%) and 46/74 thymomas (62%). PD-L1 was positive in 61/100 cases (61%) including 14/26 thymic carcinomas (54%) and 47/74 thymomas (64%). A total of 82 cases (82%) showed expression of PD-1 or PD-L1. PD-1+ cases were associated with higher stage in thymic carcinoma (P=0.01) and PD-1− cases with thymic carcinoma histology (P=0.0014), whereas PD-L1+ cases were associated with neoadjuvant therapy in thymoma (P=0.0065). There was no statistical difference between PD-1 or PD-L1 expression status and other clinicopathological parameters including overall survival. PD-1 and/or PD-L1 are expressed in up to 82% of thymic epithelial neoplasms. These results confirm that these tumors should be considered for PD-1/PD-L1-targeted therapy, however their predictive value in terms of prognosis remains uncertain.
This book is an unprecedented attempt to analyze the role of the law in the global movement for social justice. Case studies in the book are written by leading scholars from both the global South and ...the global North, and combine empirical research on the ground with innovative sociolegal theory to shed new light on a wide array of topics. Among the issues examined are the role of law and politics in the World Social Forum; the struggle of the anti-sweatshop movement for the protection of international labour rights; and the challenge to neoliberal globalization and liberal human rights raised by grassroots movements in India and indigenous peoples around the world. These and other cases, the editors argue, signal the emergence of a subaltern cosmopolitan law and politics that calls for new social and legal theories capable of capturing the potential and tensions of counter-hegemonic globalization.
The re-use of previously validated designs is critical to the evolution of synthetic biology from a research discipline to an engineering practice. Here we describe the Synthetic Biology Open ...Language (SBOL), a proposed data standard for exchanging designs within the synthetic biology community. SBOL represents synthetic biology designs in a community-driven, formalized format for exchange between software tools, research groups and commercial service providers. The SBOL Developers Group has implemented SBOL as an XML/RDF serialization and provides software libraries and specification documentation to help developers implement SBOL in their own software. We describe early successes, including a demonstration of the utility of SBOL for information exchange between several different software tools and repositories from both academic and industrial partners. As a community-driven standard, SBOL will be updated as synthetic biology evolves to provide specific capabilities for different aspects of the synthetic biology workflow.
This article provides a comprehensive review of power grid resilience, including current metrics and definitions, as well as the procedures used to ensure and improve the resilience of a system. We ...also describe the different strategies used by users to ensure their own resilience. Additionally, this article highlights areas for future research and opportunities for the integration of emerging technologies such as computer vision. The main objective of this study was to explore the metrics and strategies used in power grids and for the users to improve and ensure resilience in case of events.
EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative ...(HER2-) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2- BC patients in the GEICAM 9906 trial.
The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor-positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.
The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2- tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2- cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.
EP is an independent prognostic parameter in node-positive, ER+/HER2- BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.
Spindle cell and pleomorphic carcinomas are currently grouped among sarcomatoid carcinomas of the lung. Due to their unusual occurrence, these tumors have not been properly assessed by ...immunohistochemistry. We performed a comprehensive immunohistochemical analysis of 86 of these tumors. Seventy-four pleomorphic carcinomas (57 with differentiated elements) and 12 spindle cell carcinomas were subjected to immunohistochemistry with CAM5.2, cytokeratin 7 (CK7), thyroid transcription factor 1 (TTF-1), napsin A, CK5/6, p40, desmocollin-3, Sox2, calretinin, and D2–40. The percentage of positive tumor cells as well as the staining intensity were evaluated and scored. The spindle/giant elements were positive for CAM5.2 (93%), CK7 (79%), TTF-1 (41%), napsin A (20%), calretinin (20%), Sox2 (13%), CK5/6 (9%), p40 (8%), D2–40 (6%) and desmocollin-3 (3%). Twenty-one of 29 cases (72%) in which immunohistochemistry was performed on spindle/giant cell and corresponding differentiated elements showed a consistent staining pattern in both components while in 8 cases (28%) the immunophenotype in the spindle/giant cells was less lineage-specific than in the differentiated component. Therefore, we consider that 42% of neoplasms otherwise classified as sarcomatoid carcinoma can be reclassified as adenocarcinoma and 14% as squamous cell carcinoma while the remaining 44% failed to show a more specific immunophenotype. The use of a comprehensive immunohistochemical panel allows reclassification of the majority of sarcomatoid carcinomas as poorly differentiated variants of adenocarcinoma or squamous cell carcinoma. Such reclassification will facilitate clinical management, allow molecular testing and pursuit of targeted treatment strategies. Application of immunohistochemistry should become the standard in the workup of pulmonary sarcomatoid carcinomas.
Abstract
The flow of water through a horizontal small-scale Venturi tube of rectangular cross-section is simulated using a modified version of the open-source code DualSPHysics, which is based on ...Smoothed Particle Hydrodynamics (SPH) methods. Water is simulated using the Murnaghan-Tait equation of state so that weak compressibility is allowed. The hydrodynamics is coupled to a Large-Eddy Simulation (LES) turbulence model. The convergence properties of SPH are improved by adopting a C
$$^{2}$$
2
Wendland function as the interpolation kernel, increased number of neighboring particles and non-reflective open boundary conditions at the outlet of the Venturi tube. The flow structure and differential pressure as well as the mainstream velocity profiles at different stations are compared with calibrated experimental data. A resolution independence test shows that good convergence to the experimental measurements is achieved using four million particles. At this resolution the simulations predict the experimental centerline velocity profile along the Venturi meter for a volumetric flow rate of ten liters per minutes (lpm) with a root-mean-square error of 4.3%. This error grows to 7.1% when the volumetric flow rate increases to 25 lpm. The predicted differential pressure matches the experimental data with errors varying from 1.4% (for 10 lpm) to 6.8% (for 25 lpm). Cross-sectional velocity profiles within the throat and divergent sections differ from the experimental measurements in less than 5.5%. In general, it is shown that the SPH model can provide an efficient and accurate method for recalibrating flow meters at moderately high Reynolds numbers instead of using costly experimental tests.
Finite-set model-predictive control (FS-MPC) has many advantages, such as a fast dynamic response and an intuitive implementation. For these reasons, it has been thoroughly researched during the last ...decade. However, the waveform produced by FS-MPC has a switching component whose spread spectrum remains a major disadvantage of the strategy. This paper discusses a modulated model-predictive control that guarantees a spectrum switching frequency in the linear modulation range and extends its optimized response to the overmodulation region. Due to the equivalent high gain of the predictive control and to the limit on the voltage actuation of the power converter, it is expected that the actuation voltage will enter the overmodulation region during the large reference changes or in response to load impacts. An optimized overmodulation strategy that converges toward the FS-MPC 's response for large tracking errors is proposed for this situation. This technique seamlessly combines PWM's good steady-state switching performance with FS-MPC 's high dynamic response during large transients. The constant switching frequency is achieved by incorporating modulation of the predicted current vectors in the model-predictive control of the currents in a similar fashion as the conventional space-vector pulsewidth modulation is used to synthesize an arbitrary voltage reference. Experimental results showing the proposed strategy's good steady-state switching performance, its FS-MPC -like transient response, and the seamless transition between modes of operation are presented for a permanent magnet synchronous machine drive.
The heat and capsaicin receptor TRPV1 channel is widely expressed in nerve terminals of dorsal root ganglia (DRGs) and trigeminal ganglia innervating the body and face, respectively, as well as in ...other tissues and organs including central nervous system. The TRPV1 channel is a versatile receptor that detects harmful heat, pain, and various internal and external ligands. Hence, it operates as a polymodal sensory channel. Many pathological conditions including neuroinflammation, cancer, psychiatric disorders, and pathological pain, are linked to the abnormal functioning of the TRPV1 in peripheral tissues. Intense biomedical research is underway to discover compounds that can modulate the channel and provide pain relief. The molecular mechanisms underlying temperature sensing remain largely unknown, although they are closely linked to pain transduction. Prolonged exposure to capsaicin generates analgesia, hence numerous capsaicin analogs have been developed to discover efficient analgesics for pain relief. The emergence of
tools offered significant techniques for molecular modeling and machine learning algorithms to indentify druggable sites in the channel and for repositioning of current drugs aimed at TRPV1. Here we recapitulate the physiological and pathophysiological functions of the TRPV1 channel, including structural models obtained through cryo-EM, pharmacological compounds tested on TRPV1, and the
tools for drug discovery and repositioning.
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