Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer ...cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals.
In this study, we examined BRAF mutation in a wide range of histiocytic and dendritic cell neoplasms and compared its detection rate in each disease group.
A total of 129 cases of histiocytic, ...dendritic cell and other related lesions were reviewed from the archives of 10 hospitals in Korea. The cases consisted of histiocytic sarcoma, follicular dendritic cell (FDC) sarcoma, interdigitating cell sarcoma, Langerhans cell histiocytosis (LCH), Langerhans cell sarcoma, blastic plasmacytoid dendritic cell neoplasm, acute monocytic leukaemia M5, giant cell tumour, xanthogranuloma, inflammatory myofibroblastic tumour and Rosai-Dorfman disease. BRAF mutation analysis was performed by Sanger sequencing and PNAcqPCR. All the detected mutations of BRAF were V600E. Histiocytic sarcoma exhibited the highest rate of BRAF(V600E) (62.5%, five of eight), followed by Langerhans cell tumours (25%, seven of 28), FDC sarcoma (18.5%, five of 27) and giant cell tumour (6.7%, two of 30). The other tumours did not harbour BRAF mutations. In histiocytic sarcoma, FDC sarcoma and LCH, there were no significant differences in clinical features between tumours containing BRAF(V600E) and those with BRAF(wt) .
BRAF(V600E) was not limited to LCH and was detected more frequently in histiocytic sarcoma. Our findings suggest that the BRAF pathway may contribute to the pathogenesis or malignant transformation of histiocytic and dendritic cell neoplasms.
Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family ...receptor α 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy. GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene RET kinase. Cisplatin-resistant osteosarcoma cells showed NFKB1/NFκB-mediated GFRA1 expression. GFRA1 expression promoted tumor formation and growth in mouse xenograft models and inhibition of autophagy in a GFRA1-expressing xenograft mouse model during cisplatin treatment effectively reduced tumor growth and increased survival. In cisplatin-treated patients, treatment period and metastatic status were associated with GFRA1-mediated autophagy. These findings suggest that GFRA1-mediated autophagy is a promising novel target for overcoming cisplatin resistance in osteosarcoma.
Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous and prevalent subtype of aggressive non‐Hodgkin lymphoma that poses diagnostic and prognostic challenges, particularly in predicting drug ...responsiveness. In this study, we used digital pathology and deep learning to predict responses to immunochemotherapy in patients with DLBCL. We retrospectively collected 251 slide images from 216 DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP), with their immunochemotherapy response labels. The digital pathology images were processed using contrastive learning for feature extraction. A multi‐modal prediction model was developed by integrating clinical data and pathology image features. Knowledge distillation was employed to mitigate overfitting on gigapixel histopathology images to create a model that predicts responses based solely on pathology images. Based on the importance derived from the attention mechanism of the model, we extracted histological features that were considered key textures associated with drug responsiveness. The multi‐modal prediction model achieved an impressive area under the ROC curve of 0.856, demonstrating significant associations with clinical variables such as Ann Arbor stage, International Prognostic Index, and bulky disease. Survival analyses indicated their effectiveness in predicting relapse‐free survival. External validation using TCGA datasets supported the model's ability to predict survival differences. Additionally, pathology‐based predictions show promise as independent prognostic indicators. Histopathological analysis identified centroblastic and immunoblastic features to be associated with treatment response, aligning with previous morphological classifications and highlighting the objectivity and reproducibility of artificial intelligence‐based diagnosis. This study introduces a novel approach that combines digital pathology and clinical data to predict the response to immunochemotherapy in patients with DLBCL. This model shows great promise as a diagnostic and prognostic tool for clinical management of DLBCL. Further research and genomic data integration hold the potential to enhance its impact on clinical practice, ultimately improving patient outcomes.
Solitary fibrous tumors (SFTs) are rare benign mesenchymal tumors that occur mainly in the pleura. We herein report the first case of a cellular SFT located in the mental region of the head and neck ...in a 46-year-old woman. Facial computed tomography revealed a mass measuring 0.8 cm with clear boundaries in the right mental region. After excision of the mass, expert pathologists diagnosed a cellular SFT. To our knowledge, this is the first case of a cellular SFT identified in the subcutaneous tissue of the mental region of the head and neck. Because the postsurgical prognosis of SFTs is unpredictable, long-term follow-up and further studies are necessary to determine the characteristics of cellular SFTs in the head and neck region.
Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 ...(APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.
Acral melanoma occurring on the palms, soles, and nails is the most common subtype of cutaneous melanoma in Asians. Genetic alterations in acral melanoma and acral melanocytic nevus are not well ...known. We performed next-generation sequencing and evaluated the correlations between genetic information and the clinicopathologic characteristics from 85 Korean patients with acral melanocytic neoplasms. Of the 64 patients with acral melanoma, most had lesions at the T2 stage or higher, and the heel was the most common anatomical site of melanoma (n = 34 53.1%). The five most common mutations were BRAF (22 34.4%), NRAS (14, 21.9%), NF1 (11, 17.2%), GNAQ (12, 17.2%), and KIT (7, 10.9%). In the 21 acral melanocytic nevi, those five gene mutations were also common. Copy number variations were also frequently detected in 75% of acral melanomas and 47.6% of acral melanocytic nevi, and amplification was more common than deletion in both lesions. BRAF mutation was associated with round epithelioid cells and NRAS and NF1 mutations with bizarre cells. NF1 and GNAQ mutations showed elongated and spindle cells with prominent dendrites in acral melanomas. KIT mutations were common in amelanotic acral melanoma. This study suggests that common mutated genes are associated with distinct cytomorphological features in acral melanocytic lesions.
Purpose
Fluorescence in situ hybridization (FISH) using tumor tissue is the gold standard for detection of anaplastic lymphoma kinase (
ALK
) rearrangement in non-small cell lung cancer (NSCLC). ...However, this method often is not repeatable due to difficulties in the acquisition of tumor tissues. Blood-based liquid biopsy using reverse transcription polymerase chain reaction (RT-PCR) is expected to be useful to overcome this limitation. Here, we investigated the feasibility of liquid biopsy using plasma and platelets for detection of
ALK
rearrangement and prediction of ALK inhibitor treatment outcomes.
Methods
ALK
-FISH assays were performed in 1128 tumor specimens of NSCLC between January 2015 and June 2018. We retrospectively analyzed formalin-fixed paraffin-embedded (FFPE) tissues from previously confirmed FISH-positive (
n
= 199) and -negative (
n
= 920) cases. We recruited patients who had available tissue specimens and agreed to venous sampling. RNA was extracted from FFPE blocks, plasma, and platelets. Fusion RNA of echinoderm microtubule-associated protein-like 4 (
EML4
)-
ALK
was detected by quantitative PCR.
Results
Thirty-three FISH-positive and 28 FISH-negative patients were enrolled. In validation, data compared with FISH, RT-PCR using FFPE tissues showed 54.5% sensitivity, 78.6% specificity, and 75.5% accuracy. Liquid biopsy had higher sensitivity (78.8%), specificity (89.3%) and accuracy (83.6%). Higher positivity for liquid biopsy was shown in subgroups with delayed (≥ 6 months from diagnosis) blood sampling (plasma, 85.7%; platelets, 87.0%). In 26 patients treated with crizotinib, the platelet-positive subgroup showed longer median duration of treatment (7.2 versus 1.5 months), longer median progression-free survival (5.7 months versus 1.7 months), a higher overall response rate (70.6% versus 11.1%), and a higher disease control rate (88.2% versus 44.4%) than the platelet-negative subgroup.
Conclusion
Liquid biopsy could have applications in the diagnosis of ALK-positive NSCLC, even when using RT-PCR, and platelets can be useful for predicting treatment outcomes of ALK inhibitors.
Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is very rare in the thyroid gland. Cytopathologists should carefully examine squamoid cluster and eosinophils in Hashimoto's thyroiditis ...to raise suspicion of SMECE.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon and aggressive hematologic malignancy that arises from plasmacytoid dendritic cells. BPDCN typically presents with skin lesions ...with or without involvement of lymph nodes, peripheral blood, or bone marrow. However, breast involvement of BPDCN is rare and there has been no report describing the radiologic features of BPDCN within breast parenchyma.
We report a case of a 47-year-old woman who presented with an incidentally detected hypermetabolic breast lesion on PET/CT with concurrent right cheek plaque.
Skin biopsy was performed for the right cheek plaque. Mammography and breast ultrasonography were performed to evaluate the breast lesion. The lesion was depicted as a 2.5 cm sized focal asymmetry on mammogram and an irregular heterogeneous echoic mass within the mammary zone of the right upper outer breast. Core needle biopsy was performed for the breast lesion. Histologic diagnosis of the two lesions was BPDCN.
The patient was treated with induction and consolidation chemotherapy and received allogenic peripheral blood stem cell transplantation.
The patient remains in complete remission state without relapse at 34 months since initial diagnosis.
This is the first case of BPDCN manifested as a breast parenchymal mass and assessed by diagnostic breast imaging tools (mammography and ultrasonography). This case report is significant for BPDCN within the breast parenchyma and presenting rare radiologic description of BPDCN.
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