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This article focuses on the widespread practice of appointing deputy judges, called naibs, in the Ottoman Empire from the mid-eighteenth to the early nineteenth centuries. Based on extensive archival research, it analyses how the judiciary turned into a system of allocating revenue sources. An increasing number of offices of kadı (judge) were assigned as a source of income to higher-ranking ulema, who, through intermediaries, in turn farmed out their judicial offices to naibs in return for a fixed sum of money. Importantly, the apportionment fees for taxes collected from local taxpayers constituted a significant part of naibs’ incomes. The practice of deputizing in the Ottoman judiciary thus shows a close parallel with tax farming. Because the naibs transferred their revenues to the higher-ranking ulema, farming out judicial offices became a major economic basis for maintaining the Ottoman ulema hierarchy.

Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.

CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate‐cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species (ROS). This mechanism confers ROS resistance to CSC and CD44v9‐expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing ROS‐mediated apoptosis. Twenty non‐pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD44v9 and xCT expression. Human HCC cell lines HAK‐1A and HAK‐1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD44v9 positivity was significantly higher in HAIC‐treated tissues (5/7) than in non‐pretreated tissues (2/30), suggesting the involvement of CD44v9 in the resistance to HAIC. xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD44v9‐harboring HAK‐1B cells through ROS‐mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS‐mediated apoptosis in CDDP‐treated HCC cells, in which the CD44v9‐xCT system functioned. As CD44v9 is typically expressed in HAIC‐resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance. This study is the first to show high expression of CD44v9, a cancer stem cell marker, in chemoresistant hepatocellular carcinoma cells, which were previously exposed to chemotherapeutic agents through hepatic arterial infusion chemoembolization.

BackgroundA histopathological growth pattern (HGP) occurs at the interface between tumor cells and the surrounding liver parenchyma. Desmoplastic HGP (dHGP) is associated with a favorable prognosis and shows denser infiltration of lymphocytes than other HGPs. Tumor-infiltrating lymphocytes (TILs) exert antitumor immunity, nonetheless, their prognostic significance in patients with dHGP is unknown. This study aimed to identify the prognostic significance of HGP and TILs in colorectal liver metastasis (CRLM).MethodsThe study analyzed 140 patients who underwent hepatectomy for CRLM. Depending on the type of HGP and TIL, the patients were categorized into four groups (dHGP/high TIL, dHGP/low TIL, non-dHGP/high TIL, and non-dHGP/low TIL) for a comparison of their recurrence-free survival (RFS) and overall survival (OS). Uni- and multivariate analyses were performed using a Cox proportional hazards model.ResultsThe RFS and OS curves differed significantly between the groups. The multivariate analysis showed that a combination of HGP and TIL could stratify the recurrence and survival outcomes.ConclusionThis study indicated that a combination of HGP and TIL can stratify the risk of survival after hepatectomy in patients with CRLM.

Osimertinib, a third-generation EGFR-TKI, has nowadays been applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M, but ultimately develop resistance to this drug. Here we report a novel mechanism of acquired resistance to osimertinib and the reversal of which could improve the clinical outcomes. In osimertinib-resistant lung cancer cell lines harboring T790M mutation that we established, expression of multiple EGFR family proteins and MET was markedly reduced, whereas expression of AXL, CDCP1 and SRC was augmented along with activation of AKT. Surprisingly, AXL or CDCP1 expression was induced by osimertinib in a time-dependent manner up to 3 months. Silencing of CDCP1 or AXL restored the sensitivity to osimertinib with reduced activation of SRC and AKT. Furthermore, silencing of both CDCP1 and AXL increased the sensitivity to osimertinib. Either silencing of SRC or dasatinib, a SRC family kinase (SFK) inhibitor, suppressed AKT phosphorylation and cell growth. Increased expression of AXL and CDCP1 was observed in refractory tumor samples from patients with lung cancer treated with osimertinib. Together, this study suggests that AXL/SFK/AKT and CDCP1/SFK/AKT signaling pathways play some roles in acquired osimertinib resistance of non-small cell lung cancer.

Background/Aim: We investigated the anti-proliferative effect of quercetin on liver cancer cell lines. Materials and Methods: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 μM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin. Results: The addition of quercetin resulted in a dose- and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle. Conclusion: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest.

Background Inflammatory indices and tumor-infiltrating lymphocytes (TILs) have prognostic value in many cancer types. This study aimed to assess the prognostic value of inflammatory indices and evaluate their correlation with survival and presence of TILs in patients with colorectal liver metastasis (CRLM). Methods Medical records of 117 patients who underwent hepatectomy for CRLM were retrospectively reviewed. We calculated inflammatory indices comprising the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, C-reactive protein/albumin ratio (CAR), and Glasgow prognostic score (GPS). Furthermore, we evaluated the relationship between these ratios and the GPS and survival rates and immunohistochemical results of tumor-infiltrating CD3+, CD8+, and Foxp3+ lymphocytes. Results The patients with low CAR values and low GPS had significantly better overall survival as per the log-rank test ( p  = 0.025 and p  = 0.012, respectively). According to the multivariate analysis using the Cox proportional hazard model, the CAR (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.33–0.99; p  = 0.048) and GPS (HR, 0.40; 95% CI, 0.19–0.83; p  = 0.013) were independent prognostic factors. Additionally, Foxp3+ lymphocytes were more common in samples from the patients with a low CAR ( p  = 0.041). Moreover, the number of CD3+ TILs was significantly higher in the patients with a low GPS ( p  = 0.015). Conclusions The CAR and GPS are simple, inexpensive, and objective markers associated with predicting survival in patients with CRLM. Moreover, they can predict the presence of Foxp3+ and CD3+ lymphocytes in the invasive margin of a tumor. Trial registration Retrospectively registered. https://www.kurume-u.ac.jp/uploaded/attachment/14282.pdf .

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.

Insulinoma-associated protein 1 (INSM1) is an important biomarker of Achaete-scute homolog-like 1-driven pathways. For diagnosis of pancreatic neuroendocrine tumors (PanNET), chromogranin A (CGA), synaptophysin (SYP), and neural cell adhesion molecule (NCAM) were also considered as potential biomarkers. However, it is often difficult to diagnose it immunohistochemically. Hence, we examined the expression pattern of INSM1 in pancreatic solid tumors. We detected INSM1, CGA, SYP, and NCAM immunohistochemically, in 27 cases of NET [pure type: 25 cases, mixed adenoneuroendocrine carcinoma (MANEC): 2 cases]. We included 5 cases of solid-pseudopapillary neoplasm (SPN), 7 cases of acinar cell carcinoma (ACC), and 15 cases of pancreatic ductal adenocarcinoma (PDAC) as the control group. Nuclear expression of INSM1 was found in all PanNET pure type cases. However, expression of INSM1 was negative in PDAC, ACC, and SPN in all cases, whereas faint expression was seen in the cytoplasm from SPN. MANEC comprises of two components: neuroendocrine carcinoma and adenocarcinoma components. The NET component was positive for INSM1 expression, whereas the PDAC component does not express INSM1, which aids in distinguishing these components. Our results suggest that INSM1 is a useful immunohistochemical marker for diagnosing pancreatic neuroendocrine tumor.