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Both combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and cholangiolocarcinoma are rare primary liver cancers. cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells. Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells. According to the 2019 revision of the World Health Organization criteria, a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory. That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA. Consequently, cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct. Herein, we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver. We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma. Furthermore, this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment. The results provide valuable insights into the mechanisms of growth, differentiation, and regulation of liver cancers.

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The existing methods of assessing the fatigue life of welded joints fail to consider local strain ranges and mean stress at the weld toe. The present work proposes a novel approach to assessing the fatigue life of welded joints by conducting measurements with digital image correlation (DIC) and X-ray diffraction (XRD) in combination. Local strain ranges at the weld toe of gusset welded joints were measured by DIC. Hammer peening was conducted on the welded joints to introduce different initial stresses. The influence of mean stress was investigated by considering initial residual stress measured by XRD and a perfect plastic material model. The fatigue experiment was carried out on specimens with and without hammer peening. The results showed that hammer peening could offset adverse welding deformation effectively, and introduce significant residual compressive stress. The fatigue failure life increased by more than 15 times due to hammer peening. The fatigue initiation life assessed by the proposed method was close to that based on nominal stress, indicating that the proposed method is reliable for predicting the fatigue initiation life of welded joints.

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Breast cancer (BCa) frequently metastasizes to the bone. BCa patients with oligometastatic bone diseases have much more favorable outcomes than those with metastatic bone disease. Radiation therapy (RT), especially stereotactic body radiation therapy (SBRT), is advised for the treatment of patients with oligometastatic bone disease in other primary sites. This line of treatment provided favorable outcomes in patients and resulted in only mild toxicities. A similar strategy has been suggested for treatment of BCa patients with oligometastatic bone disease. BCa, bone-only, or high radiation dose are reported to have been associated with good outcomes in RT for metastatic disease. Furthermore, based on the guidelines provided by the BCa expert panel of the German Society for Radiation Oncology and members of the Working Party of Gynecologic Oncology Breast Committee and in line of the results obtained in other primary sites, our group supports the use of high-dose RT or SBRT for the treatment of BCa patients with oligometastatic bone disease. Additionally, the use of magnetic resonance imaging (MRI) for proper target volume definition and three-dimensional (3D) treatment planning especially for lesions of the trunk are essential for the treatment planning of RT. Of note, several clinical trials have combined RT with immune checkpoint inhibitors for the treatment of BCa patients with metastatic disease. Based on this, we anticipate that combined RT and ICI may serve as a better treatment modality for BCa patients with oligometastatic bone disease.

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BACKGROUND: We explored whether the use of deep learning to model combinations of symptom-physical signs and objective tests, such as lung function tests and the bronchial challenge test, would improve model performance in predicting the initial diagnosis of adult asthma when compared to the conventional machine learning diagnostic method. METHODS: The data were obtained from the clinical records on prospective study of 566 adult out-patients who visited Kindai University Hospital for the first time with complaints of non-specific respiratory symptoms. Asthma was comprehensively diagnosed by specialists based on symptom-physical signs and objective tests. Model performance metrics were compared to logistic analysis, support vector machine (SVM) learning, and the deep neural network (DNN) model. RESULTS: For the diagnosis of adult asthma based on symptom-physical signs alone, the accuracy of the DNN model was 0.68, whereas that for the SVM was 0.60 and for the logistic analysis was 0.65. When adult asthma was diagnosed based on symptom-physical signs, biochemical findings, lung function tests, and the bronchial challenge test, the accuracy of the DNN model increased to 0.98 and was significantly higher than the 0.82 accuracy of the SVM and the 0.94 accuracy of the logistic analysis. CONCLUSIONS: DNN is able to better facilitate diagnosing adult asthma, compared with classical machine learnings, such as logistic analysis and SVM. The deep learning models based on symptom-physical signs and objective tests appear to improve the performance for diagnosing adult asthma.

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Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling.

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Fibronectin (FN) matrix assembly is an essential process in normal vertebrate development, which is frequently lost in tumor cells. Here we show that membrane-type 1 matrix metalloproteinase (MT1-MMP) regulates FN matrix assembly. MT1-MMP knockdown induced FN assembly in breast carcinoma cells. Ectopic expression of MT1-MMP reduced specifically the assembled FN matrix level without affecting whole FN production in fibroblasts. Treatment of fibrosarcoma HT1080 cells with dexamethasone (DEX) enhanced FN synthesis, resulting in short fibrils but not dense matrix formation. Combined treatment of DEX and MT1-MMP inhibitor accelerated FN matrix assembly, which mediated cellular adhesion and reduced cell migration and invasion. These results indicate that MT1-MMP stimulates cell migration and invasion by negatively regulating FN assembly.

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