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Abstract Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1–2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15–20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10–40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

Abstract Background Cumulative preclinical and clinical evidences showed radiotherapy might augment systemic antitumoral responses to immunotherapy for metastatic non-small cell lung cancer, but the optimal timing of combination is still unclear. The overall infiltration and exhausted subpopulations of tumor-infiltrating CD8+ T cells might be a potential biomarker indicating the response to immune checkpoint inhibitors (ICI), the alteration of which is previously uncharacterized during peri-irradiation period, while dynamic monitoring is unavailable via repeated biopsies in clinical practice. Methods Basing on tumor-bearing mice model, we investigated the dynamics of overall infiltration and exhausted subpopulations of CD8+ T cells after ablative irradiation. With the understanding of distinct metabolic characteristics accompanied with T cell exhaustion, we developed a PET radiomics approach to identify and visualize T cell exhaustion status. Results CD8+ T cell infiltration increased from 3 to 14 days after ablative irradiation while terminally exhausted populations significantly predominated CD8+ T cells during late course of this infiltrating period, indicating that 3–7 days post-irradiation might be a potential appropriate window for delivering ICI treatment. A PET radiomics approach was established to differentiate T cell exhaustion status, which fitted well in both ICI and irradiation settings. We also visualized the underlying association of more heterogeneous texture on PET images with progressed T cell exhaustion. Conclusions We proposed a non-invasive imaging predictor which accurately assessed heterogeneous T cell exhaustion status relevant to ICI treatment and irradiation, and might serve as a promising solution to timely estimate immune-responsiveness of tumor microenvironment and the optimal timing of combined therapy.

The wool oil is an indispensable assistant in the spinning process. There are many problem about useing the wool oil in wool textile factory, including the slimy skin plate, winding roller, high end breakage rate, unevenness, yarn color pollution phenomenon. In order to make good use of the wool oil, the problems of using the wool oil in the process of spinning were analyzed, from raw material clean degree and the fatty content of raw material, after dyed using the softener and smoothing agent, water quality and so on, the effect on the wool oil, the way of the operator using the wool oil. Find the causes and give solutions. Raw materials must be washed clean, after dyed don't add or less add softener and smoothing agent, using the soften water. It has certain guiding significance to the wool textile enterprises correct use the wool oil. [ABSTRACT FROM AUTHOR]

The phase of cross-correlation function of two different normal modes contains source range information, which can be extracted by warping transform due to the dispersive characteristics of the shallow water waveguide. The autocorrelation function of the received pressure or particle velocity contains both modal autocorrelation component (MAC) and modal cross-correlation component (MCC), with the former part usually treated as interference for source ranging. Because the real part of the vertical intensity flux (RPVIF) only contains MCC, a passive impulsive source ranging method based on the frequency warping transform of RPVIF with a single vector receiver in shallow water is presented. Using a waveguide-invariant-based frequency warping operator, the cross-correlation components of two different modes in the vertical intensity flux are warped into separable impulsive sequences, the time delays of which are subsequently used for source ranging. The advantages of source ranging based on warping the vertical intensity flux compared with warping the pressure autocorrelation function are pointed out, and the experiment results are also presented. [ABSTRACT FROM AUTHOR]

Sound multipath propagation is very important for target localization and identification in different acoustical zones of deep water. In order to distinguish the multipath characteristics in deep water, the Northwest Pacific Acoustic Experiment was conducted in 2015. A low-frequency horizontal line array towed at the depth of around 150 m on a receiving ship was used to receive the noise radiated by the source ship. During this experiment, a bearing-splitting phenomenon in the direct zone was observed through conventional beamforming of the horizontal line array within the frequency band 160 Hz–360 Hz. In this paper, this phenomenon is explained based on ray theory. In principle, the received signal in the direct zone of deep water arrives from two general paths including a direct one and bottom bounced one, which vary considerably in arrival angles. The split bearings correspond to the contributions of these two paths. The bearing-splitting phenomenon is demonstrated by numerical simulations of the bearing-time records and experimental results, and they are well consistent with each other. Then a near-surface source ranging approach based on the arrival angles of direct path and bottom bounced path in the direct zone is presented as an application of bearing splitting and is verified by experimental results. Finally, the applicability of the proposed ranging approach for an underwater source within several hundred meters in depth in the direct zone is also analyzed and demonstrated by simulations. [ABSTRACT FROM AUTHOR]