Thyroid hemiatrophy associated with papillary thyroid carcinoma.

PURPOSE: The present study aimed to investigate CT imaging features, pathological findings, and prognosis in patients with thyroid hemiatrophy (THA) associated with papillary thyroid carcinoma (PTC). METHODS: This retrospective study included 225 patients with histopathologically proven PTC treated by surgical resection who underwent preoperative CT scanning. On CT images, THA was defined as thyroid parenchymal hemiatrophy on the ipsilateral side of PTC. CT findings, overall survival, and disease-free survival were compared between patients with and without THA. Pathological findings were also assessed in PTCs with and without THA. RESULTS: THA was observed in 35 of 225 (16%) patients with PTC. Atrophic thyroid parenchyma was observed in the right lobe of 20 patients (57%) and in the left lobe of the remaining 15 patients (43%). With respect to the solid components within PTCs, contrast-enhanced CT attenuation (114.2 ± 18.2 vs. 126.7 ± 31.3 HU; p < 0.05) and CT attenuation change for contrast-enhanced CT minus unenhanced CT (60.2 ± 18.1 vs. 72.3 ± 31.0 HU; p < 0.05) were significantly lower in PTCs with THA than in those without THA. Histopathologically, almost all PTCs with THA (97%) had keloid-like collagen, which is broad bundles of hypocellular collagen with bright eosinophilic hyalinization, typically observed in keloid. However, no significant differences were observed in the prognosis between the two groups. CONCLUSION: THA was occasionally observed in patients with PTC. Weak contrast-enhancement was distinct characteristic of PTC patients with THA, which is probably caused by keloid-like collagen.

Pancreatic cancer detection with dual-energy CT: diagnostic performance of 40 keV and 70 keV virtual monoenergetic images.

PURPOSE: To compare the diagnostic performance of 40 keV and 70 keV virtual monoenergetic images (VMIs) generated from dual-energy CT in the detection of pancreatic cancer. METHODS: This retrospective study included patients who underwent pancreatic protocol dual-energy CT from January 2019 to August 2022. Four radiologists (1-11 years of experience), who were blinded to the final diagnosis, independently and randomly interpreted 40 keV and 70 keV VMIs and graded the presence or absence of pancreatic cancer. For each image set (40 keV and 70 keV VMIs), the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. The diagnostic performance of each image set was compared using generalized estimating equations. RESULTS: Overall, 137 patients (median age, 71 years; interquartile range, 63-78 years; 77 men) were included. Among them, 62 patients (45%) had pathologically proven pancreatic cancer. The 40 keV VMIs had higher specificity (75% vs. 67%; P < .001), PPV (76% vs. 71%; P < .001), and accuracy (85% vs. 81%; P = .001) than the 70 keV VMIs. On the contrary, 40 keV VMIs had lower sensitivity (96% vs. 98%; P = .02) and NPV (96% vs. 98%; P = .004) than 70 keV VMIs. However, the diagnostic confidence in patients with (P < .001) and without (P = .001) pancreatic cancer was improved in 40 keV VMIs than in 70 keV VMIs. CONCLUSIONS: The 40 keV VMIs showed better diagnostic performance in diagnosing pancreatic cancer than the 70 keV VMIs, along with higher reader confidence.

Comparison of image quality and pancreatic ductal adenocarcinoma conspicuity between the low-kVp and dual-energy CT reconstructed with deep-learning image reconstruction algorithm.

PURPOSE: To compare the image quality and conspicuity of pancreatic ductal adenocarcinoma (PDAC) between the low-kVp and dual-energy pancreatic protocol CT reconstructed with deep-learning image reconstruction (DLIR). METHOD: A cohort of 111 consecutive patients (median age, 72 years; 56 men) undergoing a pancreatic protocol CT were retrospectively analyzed. Among them, 58 patients underwent 80-kVp CT (80-kVp group), and 53 patients underwent dual-energy CT and reconstructed at 40-keV (40-keV group). The medium-strength level of DLIR were used in both groups. Quantitative measurements, qualitative image quality, PDAC conspicuity, and dose-length product (DLP) were compared between the two groups using Mann-Whitney U test. RESULTS: A total of 20 and 16 PDACs were found in the 80-kVp and 40-keV groups, respectively. CT numbers of the vasculatures and parenchymal organs (P <.001 for all) and the background noise at both pancreatic and portal venous phases (P <.001) were higher in the 40-keV group than in the 80-kVp group. The signal-to-noise ratio (SNR) of all anatomical structures (P <.001-0.005), except for the liver in reviewer 2 (P =.47), and the tumor-to-pancreas contrast-to-noise ratio (CNR; P <.001-0.01) were higher in the 40-keV group than in the 80-kVp group. No difference was found in the image quality at both phases (P =.30-0.90). PDAC conspicuity was better in the 40-keV group than in the 80-kVp group (P =.007-0.03). DLP at pancreatic (275 vs. 313 mGy*cm; P =.05) and portal venous phases (743 vs. 766 mGy*cm; P =.20) was comparable between the two groups. CONCLUSION: Under the same DLP, virtual monoenergetic images at 40-keV demonstrated higher SNR and tumor-to-pancreas CNR and better PDAC conspicuity compared to the 80-kVp setting.

Isolation of balenine from opah (Lampris megalopsis) muscle and comparison of antioxidant and iron-chelating activities with other major imidazole dipeptides.

Balenine (Bal) in opah muscle was extracted using hot water and purified by ion-exchange chromatography and recrystallization to provide 41 g of over 95% pure Bal from 1 kg of opah muscle. The structure of purified Bal was identical to that of an authentic Bal standard by NMR analysis. The antioxidant (ORAC and HORAC values) and Fe(II) ion-chelating abilities of purified Bal were examined by comparison with two major imidazole dipeptides, carnosine (Car) and anserine (Ans). Opah-derived Bal showed significantly higher ORAC and HORAC values and Fe(II) ion-chelating ability at 0.3 mM. In silico molecular simulation revealed that Bal and Car formed hydrogen bonds between the hydrogen atom of the imidazole imino group and the carboxyl carbonyl oxygen, whereas Ans did not. The proposed method for extracting and purifying Bal from opah muscle suggests that opah can be utilized as a functional food or Bal resource.

Dietary Supplementation of Selenoneine-Containing Tuna Dark Muscle Extract Effectively Reduces Pathology of Experimental Colorectal Cancers in Mice.

Selenoneine is an ergothioneine analog with greater antioxidant activity and is the major form of organic selenium in the blood, muscles, and other tissues of tuna. The aim of this study was to determine whether a selenoneine-rich diet exerts antioxidant activities that can prevent carcinogenesis in two types of colorectal cancer model in mice. We administrated selenoneine-containing tuna dark muscle extract (STDME) to mice for one week and used azoxymethane (AOM) and dextran sodium sulfate (DSS) for inducing colorectal carcinogenesis. Next, we examined the incidence of macroscopic polyps and performed functional analysis of immune cells from the spleen. In the AOM/DSS-induced colitis-associated cancer (CAC) model, the oral administration of STDME significantly decreased tumor incidence and inhibited the accumulation of myeloid-derived suppressor cells (MDSCs) while also inhibiting the downregulation of interferon-γ (IFN-γ) production during carcinogenesis. These results suggest that dietary STDME may be an effective agent for reducing colorectal tumor progression.

Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives.

The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.

Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.

Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.

Discovery of novel S1P2 antagonists. Part 1: discovery of 1,3-bis(aryloxy)benzene derivatives.

The structure-activity relationships of a novel series of sphingosine-1-phosphate receptor antagonists have been examined in detail. The initial hit compound 1 was modified through synthesis to improve its S1P2 activity. The synthesis of a series of analogs revealed that 1,3-bis(aryloxy)benzene derivatives, as represented by 22, are potent and selective S1P2 antagonists.

Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors.

Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington's disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we designed and prepared a series of 2-anilinobenzamide analogues. Enzyme assays using recombinant SIRT1 and SIRT2 revealed that 3'-phenethyloxy-2-anilinobenzamide analogues such as 33a and 33i are potent and selective SIRT2 inhibitors, showing more than 3.5-fold greater SIRT2-inhibitory activity and more than 35-fold greater SIRT2-selectivity compared with AGK2 (3), a previously reported SIRT2-selective inhibitor. Compound 33a also induced a dose-dependent selective increase of α-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. These 3'-phenethyloxy-2-anilinobenzamide derivatives represent an entry into a new class of SIRT2-selective inhibitors.

Structure-activity study of L-amino acid-based N-type calcium channel blockers.

Synthesis and structure-activity relationship (SAR) study of L-amino acid-based N-type calcium channel blockers are described. The compounds synthesized were evaluated for inhibitory activity against both N-type and L-type calcium channels focusing on selectivity to reduce cardiovascular side effects due to blocking of L-type calcium channels. In the course of screening of our compound library, N-(t-butoxycarbonyl)-L-aspartic acid derivative 1a was identified as an initial lead compound for a new series of N-type calcium channel blockers, which inhibited calcium influx into IMR-32 human neuroblastoma cells with an IC(50) of 3.4 microM. Compound 1a also exhibited blockade of N-type calcium channel current in electrophysiological experiment using IMR-32 cells (34% inhibition at 10 microM, n=3). As a consequence of conversion of amino acid residue of 1a, compound 12a, that include N-(t-butoxycarbonyl)-L-cysteine, was found to be a potent N-type calcium channel blocker with an IC(50) of 0.61 microM. Thus, L-cysteine was selected as a potential structural motif for further modification. Optimization of C- and N-terminals of L-cysteine using S-cyclohexylmethyl-L-cysteine as a central scaffold led to potent and selective N-type calcium channel blocker 21f, which showed improved inhibitory potency (IC(50) 0.12 microM) and 12-fold selectivity for N-type calcium channels over L-type channels.

L-Cysteine based N-type calcium channel blockers: structure-activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models.

This study was performed to determine the structure-activity relationships (SAR) of L-cysteine based N-type calcium channel blockers. Basic nitrogen was introduced into the C-terminal lipophilic moiety of L-cysteine with a view toward improvement of its physicochemical properties. L-Cysteine derivative 9 was found to be a potent and selective N-type calcium channel blocker with IC(50) of 0.33 microM in calcium influx assay using IMR-32 cells and was 15-fold selective for N-type calcium channels over L-type channels. Compound 9 showed improved oral analgesic efficacy in the rat formalin induced pain model and the rat chronic constriction injury (CCI) model, which is one of the most reliable models of chronic neuropathic pain, without any significant effect on blood pressure or neurological behavior.

Structure-activity study of L-cysteine-based N-type calcium channel blockers: optimization of N- and C-terminal substituents.

Synthesis and structure-activity relationship (SAR) studies of L-cysteine-based N-type calcium channel blockers are described. In the course of exploring SAR of the N- and C-terminal substituents, the L-cysteine derivative was found to be a potent N-type calcium channel blocker with an IC(50) value of 0.14 microM on IMR-32 assay. Compound showed 12-fold selectivity for N-type over L-type calcium channels on AtT-20 assay.