Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAF^V600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAF^V600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors.

Preoperative differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) remains an unsolved puzzle. Patients sometimes undergo unnecessary lobectomy for histology confirmation inevitably. In this retrospective study, we propose new gray-scale ultrasonographic (US) features that may help to differentiate FTC from FA. Medical charts and US images of follicular thyroid neoplasms were collected prospectively. Gray-scale US features including conventional parameters adding tubercle-in-nodule and trabecular formation were recorded. The histopathologic diagnosis was FA in 139 and FTC in 49 patients. In patients with FTC, minimally invasive follicular carcinoma (MIFC) was seen in 36 patients and widely invasive follicular carcinoma (WIFC) in 13. The incidences of calcifications (p < 0.0001), tubercle-in-nodule signs (p < 0.0001), spiculated margins (p = 0.014), and trabecular formations (p = 0.03) were significantly higher in FTC. Tubercle-in-nodule (p < 0.01) and calcification (p < 0.001) were independent factors in the differentiation of FTC in multivariate analysis (area under the curve = 0.689). US characteristics of tubercle-in-nodule in combination with calcification help to differentiate FTC from FA.

Background. This study evaluated the impact of different doses of Astragalus polysaccharides (APS) on the functional status and phenotype of T cells during polymicrobial sepsis. Methods. On day 1 after cecal ligation and puncture, mice were treated with either saline, 100 (A100), 200 (A200), or 400 mg APS/kg body weight (BW) (A400) by an intraperitoneal injection daily for 4 days. All mice were sacrificed 5 days after the operation. Results. APS treatment reversed the sepsis‐induced decrement in the T helper (Th) cell population, and the percentage of activated Th cells also increased in the spleen and Peyer’s patches. APS administration downregulated the percentages of circulating Th2 cells and regulatory T cells (Treg), and the percentage of Th17 cells in blood was upregulated in the A400 group. Weight loss and kidney injury were attenuated in the A100 and A200 groups but not in the A400 group at the end of the study. Conclusions. Treatments with 100 and 200 mg APS/kg BW reduced Treg populations and elicited a more‐balanced Th1/Th2 response that consequently attenuated immunosuppression in polymicrobial sepsis. High‐dose APS administration led to excessive responses of Th17 cells which may have adverse effects in sepsis‐induced organ injury.

Hypoechogenicity has been described qualitatively and is potentially subject to intra- and inter-observer variability. The aim of this study was to clarify whether quantitative echoic indexes (EIs) are useful for the detection of malignant thyroid nodules. Overall, 333 participants with 411 nodules were included in the final analysis. Quantification of echogenicity was performed using commercial software (AmCAD-UT; AmCad BioMed, Taiwan). The coordinates of three defined regions, the nodule, thyroid parenchyma, and strap muscle regions, were recorded in the database separately for subsequent analysis. And the results showed that ultrasound echogenicity (US-E), as assessed by clinicians, defined hypoechogenicity as an independent factor for malignancy. The EI, adjusted EI (EI_N-T; EI_N-M) and automatic EI_(N-R)/R values between benign and malignant nodules were all significantly different, with lower values for malignant nodules. All of the EIs showed similar percentages of sensitivity and specificity and had better accuracies than US-E. In conclusion, the proposed quantitative EI seems more promising to constitute an important advancement than the conventional qualitative US-E in allowing for a more reliable distinction between benign and malignant thyroid nodules.

The present study investigated the effects of glutamine (GLN) pretreatment on CD4⁺T cell polarisation and remote kidney injury in mice with gut-derived polymicrobial sepsis. Mice were randomly assigned to three groups: normal control fed with American Institute of Nutrition (AIN)-93G diet and two sepsis groups provided with either AIN-93G-based diet or identical components, except part of casein was replaced by GLN. Mice were given their respective diets for 2 weeks. Then, mice in the sepsis groups were performed with caecal ligation and puncture and were killed 72 h after the surgery. Blood, spleens and kidneys were collected for further examination. The results showed that sepsis resulted in decreased circulating and splenic total T lymphocyte and CD4⁺T cell percentages, whereas IL-4-, and forkhead box p3 (Foxp3)-expressing CD4⁺T cells percentages were up-regulated. Compared with the sepsis control group, pretreatment with GLN maintained blood T and CD4⁺T cells and reduced percentages of IL-4- and Foxp3-expressing CD4⁺T cells. Also, a more pronounced activation and increased anti-apoptotic Bcl-2 gene expression of splenic CD4⁺T cells were observed. Concomitant with the decreased plasma IL-6, keratinocyte-derived chemokine (KC) levels, the gene expression of KC, macrophage inflammatory protein-2 and renal injury biomarker kidney injury molecule-1 (Kim-1) were down-regulated when GLN was administered. These findings suggest that antecedent of GLN administration elicit a more balanced blood T helper cell polarisation, sustained T cell populations, prevented splenic CD4⁺T cell apoptosis and attenuated kidney injury at late phase of polymicrobial sepsis. GLN may have benefits in subjects at risk of abdominal infection.