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Patients with pancreaticobiliary maljunction (PBM) have a high risk of biliary tract cancer (BTC). The risk of pancreatic cancer is also reported to be higher in patients with PBM compared to the general population; the underlying cause remains unclear. We report a 73-year-old man with widespread pancreatic cancer involving the entire pancreas. The patient previously underwent curative resection for gallbladder cancer and hilar cholangiocarcinoma concomitant with PBM. A total pancreatectomy was performed for the new pancreatic lesion. Histopathological examination revealed a papillary tumor predominantly composed of intraepithelial lesions that extended throughout the pancreatic duct, with skip lesions and irregular invasive foci at multiple sites within the duct. The morphological features and mucin profile were similar to those of the previous biliary lesions. Genetic analysis of the current lesion showed wild-type KRAS, GNAS, and PIK3CA genes consistent with the previous lesions, indicating that the pancreatic and biliary lesions were molecularly identical clones. Based on the clinicopathological findings and molecular analysis, we concluded that the BTC had spread intraluminally to the pancreatic duct through the common channel of the PBM, resulting in intraductal dissemination. Patients with PBM should be followed for pancreatic lesions, because of the risk of intraductal dissemination of BTC., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflicts of interest to disclose. Human and animal rights: This study have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its subsequent amendments. Informed consent: Informed consent was obtained from the patient for being included in this case report., (© 2025. The Author(s), under exclusive licence to Japanese Society of Gastroenterology.)

Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)., Methods: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm., Results: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332)., Conclusion: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. However, the mechanisms underlying these variations in signaling activity by allosteric modulators remain largely elusive. Here, we determine the three-dimensional structure of the μ-opioid receptor (MOR), a class A GPCR, in complex with the G i protein and an allosteric modulator, BMS-986122, using cryogenic electron microscopy. Our results reveal that BMS-986122 binding induces changes in the map densities corresponding to R167 3.50 and Y254 5.58 , key residues in the structural motifs conserved among class A GPCRs. Nuclear magnetic resonance analyses of MOR in the absence of the G i protein reveal that BMS-986122 binding enhances the formation of the interaction between R167 3.50 and Y254 5.58 , thus stabilizing the fully-activated conformation, where the intracellular half of TM6 is outward-shifted to allow for interaction with the G i protein. These findings illuminate that allosteric modulators like BMS-986122 can potentiate receptor activation through alterations in the conformational dynamics in the core region of GPCRs. Together, our results demonstrate the regulatory mechanisms of GPCRs, providing insights into the rational development of therapeutics targeting GPCRs., (© 2024. The Author(s).)

Trace elements are minerals that are present in very low concentrations in the human body and yet are crucial for a wide range of physiological functions. Zinc, the second most abundant trace element, is obtained primarily from the diet. After being taken up in the intestine, zinc is distributed to various target organs, where it plays key roles in processes such as immunity, protein folding, apoptosis, and antioxidant activity. Given the important role of zinc in a wide range of enzymatic reactions and physiological processes, zinc deficiency has been identified in a variety of diseases, notably cancer. In recent years, multiple meta-analyses and reviews looking at zinc levels in individual cancer types have been published, as have a plethora of primary studies demonstrating a link between low zinc levels and specific types of cancer. In this review, we summarize recent evidence implicating low zinc concentrations in serum or tissues as a characteristic in a wide range of cancers. We also discuss preliminary findings indicating that zinc level measurement could ultimately become a useful clinical tool for cancer diagnosis and predicting outcomes in patients with cancer. Finally, we suggest future directions for further elucidating the role of zinc deficiency in cancer development and progression., (© 2023. The Author(s).)

An extreme thermophilic bacterium, Thermus thermophilus produces more than 20 unusual polyamines, but their biosynthetic pathways, including homospermidine, are not yet fully understood. Two types of homospermidine synthases have been identified in plants and bacteria, which use spermidine and putrescine or two molecules of putrescine as substrates. However, homospermidine synthases with such substrate specificity have not been identified in T. thermophilus. Here we identified a novel agmatine homocoupling enzyme that is involved in homospermidine biosynthesis in T. thermophilus. The reaction mechanism is different from that of a previously described homospermidine synthase, and involves conjugation of two molecules of agmatine, which produces a diamidino derivative of homospermidine (caldomycin) as an immediate precursor of homospermidine. We conclude that there is a homospermidine biosynthetic pathway from agmatine via caldomycin synthase followed by ureohydrolase in T. thermophilus. Furthermore, it is shown that caldomycin is a novel compound existing in nature., (© 2024. The Author(s).)

Background: Polyunsaturated fatty acids (PUFA) can be beneficial in the management of canine atopic dermatitis (cAD). A commercial product PCSO-524 containing PUFA has demonstrated anti-inflammatory effects in dogs., Hypothesis/objectives: To evaluate the efficacy of PCSO-524, in combination with oclacitinib in dogs with cAD., Animals: Seventeen client-owned dogs with cAD., Materials and Methods: A randomised, double-blinded, controlled trial. All dogs were treated with oclacitinib (0.4-0.6 mg/kg) twice a day for 14 days, then once a day until Day (D)42. They were randomly divided into two groups: PCSO-524 (n = 9) and sunflower oil (n = 8). Clinical status was assessed by Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and pruritus Visual Analog Scale (pVAS) at baseline (D0), D14, D28 and D42. Trans epidermal water loss (TEWL) was measured at the same time points., Results: CADESI scores decreased significantly after treatment and there was a significant difference between the PCSO-524 and the control group at D28 (p = 0.04) and D42 (p = 0.03). The PCSO-524 group also demonstrated a significantly decreased pVAS on D28 and D42 (p < 0.001 and p < 0.001) compared to D0, while significant differences were observed in the control group at D14 and D28 (p < 0.01 and p = 0.04) and not at D42 (p = 0.12). The mean TEWL showed a significant decrease at D28 and D42 in the PCSO-524 group, compared to the control group (p = 0.002 and p < 0.001)., Conclusions and Clinical Relevance: The combination of PCSO-524 and oclacitinib may help to alleviate the rebound effect that occurs when tapering down the dosage of oclacitinib, as compared to using oclacitinib alone for the management of cAD., (© 2023 The Authors. Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of ESVD and ACVD.)