APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Value function assessment to different RL algorithms for heparin treatment policy of patients with sepsis in ICU.

Heparin is a critical aspect of managing sepsis after abdominal surgery, which can improve microcirculation, protect organ function, and reduce mortality. However, there is no clinical evidence to support decision-making for heparin dosage. This paper proposes a model called SOFA-MDP, which utilizes SOFA scores as states of MDP, to investigate clinic policies. Different algorithms provide different value functions, making it challenging to determine which value function is more reliable. Due to ethical restrictions, we cannot test all policies on patients. To address this issue, we proposed two value function assessment methods: action similarity rate and relative gain. We experimented with heparin treatment policies for sepsis patients after abdominal surgery using MIMIC-IV. In the experiments, TD(0) shows the most reliable performance. Using the action similarity rate and relative gain to assess AI policy from TD(0), the agreement rates between AI policy and "good" physician's actual treatment are 64.6% and 73.2%, while the agreement rates between AI policy and "bad" physician's actual treatment are 44.1% and 35.8%, the gaps are 20.5% and 37.4%, respectively. External validation using action similarity rate and relative gain based on eICU resulted in agreement rates of 61.5% and 69.1% with the "good" physician's treatment, and 45.2% and 38.3% with the "bad" physician's treatment, with gaps of 16.3% and 30.8%, respectively. In conclusion, the model provides instructive support for clinical decisions, and the evaluation methods accurately distinguish reliable and unreasonable outcomes.

Exosomal transfer of miR-548aq-3p confers cisplatin resistance via MED12 downregulation in epithelial ovarian cancer.

OBJECTIVE: The RNA polymerase II mediator complex subunit 12 (MED12) is an important factor for chemotherapy sensitivity. We explored the roles of exosomal transfer of carcinogenic microRNAs (miRNAs) in MED12 regulation and cisplatin resistance of ovarian cancer cells. In this study, the correlation between MED12 expression and cisplatin resistance was analyzed in ovarian cancer cells. The molecular regulation of MED12 by exosomal miR-548aq-3p was investigated by bioinformatics analysis and luciferase reporter assays. Further clinical significance of miR-548aq was assessed with TCGA data. We identified decreased MED12 expression in cisplatin-resistance of ovarian cancer cells. More importantly, coculture with cisplatin-resistant cells attenuated cisplatin sensitivity of parental ovarian cancer cells, as well as reduced MED12 expression to a large extent. Further bioinformatic analysis identified that exosomal miR-548aq-3p was correlated with MED12 transcriptional regulation in ovarian cancer cells. Luciferase reporter assays demonstrated that miR-548aq-3p down-regulated MED12 expression. miR-548aq-3p overexpression enhanced cell survival and proliferation of ovarian cancer cells with cisplatin treatment, while miR-548aq-3p inhibition induced cell apoptosis of cisplatin-resistant cells. Further clinical analysis indicated that miR-548aq was correlated with lower MED12 expression. More importantly, miR-548aq expression was a detrimental factor in the disease progression of ovarian cancer patients. In conclusion, we found that miR-548aq-3p contributed to cisplatin chemotherapy resistance of ovarian cancer cells through MED12 downregulation. Our study supported miR-548aq-3p as a promising therapeutic target for improving chemotherapy sensitivity of ovarian cancer.

Radiomics nomogram for preoperative differentiation of early-stage serous borderline ovarian tumors and serous malignant ovarian tumors.

Objectives: This study aimed to construct a radiomics nomogram and validate its performance in the preoperative differentiation between early-stage (I and II) serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs). Methods: Data were collected from 80 patients with early-stage SBOTs and 102 with early-stage SMOTs (training set: n = 127; validation set: n = 55). Univariate and multivariate analyses were performed to identify the independent clinicoradiological factors. A radiomics signature model was constructed using radiomics features extracted from multidetector computed tomography images of the venous phase, in which the least absolute shrinkage and selection operator regression was employed to lessen the dimensionality of the data and choose the radiomics features. A nomogram model was established by combining independent clinicoradiological factors with the radiomics signature. The performance of nomogram calibration, discrimination, and clinical usefulness was evaluated using training and validation sets. Results: In terms of clinicoradiological characteristics, age (p = 0.001), the diameter of the solid component (p = 0.009), and human epididymis protein 4 level (p < 0.001) were identified as the independent risk factors of SMOT, for which the area under the curves (AUCs) were calculated to be 0.850 and 0.836 in the training and validation sets, respectively. Nine features were finally selected to construct the radiomics signature model, which exhibited AUCs of 0.879 and 0.826 for the training and validation sets, respectively. The nomogram model demonstrated considerable calibration and discrimination with AUCs of 0.940 and 0.909 for the training and validation sets, respectively. The nomogram model displayed more prominent clinical usefulness than the clinicoradiological and radiomics signature models according to the decision curve analysis. Conclusions: The nomogram model can be employed as an individualized preoperative non-invasive tool for differentiating early-stage SBOTs from SMOTs.

Clinicopathological, Radiological, and Molecular Features of Primary Lung Adenocarcinoma with Morule-Like Components.

BACKGROUND: Morule-like component (MLC) was a rare structure in primary lung adenocarcinoma. We aimed to reveal the clinicopathological, radiological, immunohistochemical, and molecular features of lung adenocarcinoma with MLCs. METHODS: Twenty lung adenocarcinomas with MLCs were collected, and computed tomographic and histological documents were reviewed. Immunohistochemistry, targeted next-generation sequencing, and Sanger sequencing for ß-catenin gene were performed. RESULTS: There were 9 lepidic adenocarcinomas, 8 acinar adenocarcinomas, 2 papillary adenocarcinomas, and 1 minimally invasive adenocarcinoma. Most patients (16/17) were shown a pure solid nodule, and 1 patient was shown a partly solid nodule on chest computed tomography (CT). Nine cases were accompanied with micropapillary components, and 3 were with cribriform components in which 2 suffered a worse prognosis. No significant association was found between the MCLs and the overall survival of lung adenocarcinoma (P = 0.109). The MLCs were often arranged in whorled or streaming patterns. The cells in MLCs showed syncytial and mild appearance. The MLCs were positive for E-cadherin, CK7, TTF-1, napsin-A, vimentin, and ß-catenin (membrane), and negative for CK5/6, p40, p63, Synaptophysin, chromogranin A, and Cdx-2. EGFR mutation, ALK-EML4 fusion, HER2 amplification, and PIK3CA mutation were detected in 16 cases, 2 cases, 1 case, and 1 case, respectively. EGFR mutation was more frequent in adenocarcinomas with MLCs than those without MLCs (P = 0.040). ß-catenin gene mutation was not detected in any patients. CONCLUSIONS: MLC is often observed in the background of acinar, lepidic, and papillary adenocarcinomas. Lung adenocarcinomas with MLCs tend to appear as a solid mass on CT and harbor EGFR gene mutations. The micropapillary components and cribriform components may cause poor prognosis of lung adenocarcinomas with MLCs. Vimentin is always positive in MLCs, and it is a useful marker for the identification of MLCs.

Gastrointestinal-type chemotherapy prolongs survival in an atypical primary ovarian mucinous carcinoma: A case report.

BACKGROUND: Primary ovarian mucinous carcinoma is a rare histologic subtype of epithelial ovarian carcinoma and exhibits considerable morphologic overlap with secondary tumour. It is hard to differentiate primary from metastatic ovarian mucinous carcinoma by morphological and immunohistochemical features. Because of the histologic similarity between primary ovarian mucinous carcinoma and metastatic gastrointestinal carcinoma, it has been hypothesized that ovarian mucinous carcinomas might respond better to non-gynecologic regimens. However, the standard treatment of advanced ovarian mucinous carcinoma has not reached a consensus. CASE SUMMARY: A 56-year-old postmenopausal woman presented with repeated pain attacks in the right lower quadrant abdomen, accompanied by diarrhoea, anorexia, and weight loss for about 3 mo. The patient initially misdiagnosed as having gastrointestinal carcinoma because of similar pathological features. Based on the physical examination, tumour markers, imaging tests, and genetic tests, the patient was clinically diagnosed with ovary mucinous adenocarcinoma. Whether gastrointestinal-type chemotherapy or gynecologic chemotherapy was a favourable choice for patients with advanced ovarian mucinous cancer had not been determined. The patient received a chemotherapy regimen based on the histologic characteristics rather than the tumour origin. The patient received nine cycles of FOLFOX and bevacizumab. This was followed by seven cycles of bevacizumab maintenance therapy for 9 mo. Satisfactory therapeutic efficacy was achieved. CONCLUSION: The genetic analysis might be used in the differential diagnosis of primary ovarian mucinous carcinoma and non-gynecologic mucinous carcinoma. Moreover, primary ovarian mucinous carcinoma patients could benefit from gastrointestinal-type chemotherapy.

MDCT-Based Radiomics Features for the Differentiation of Serous Borderline Ovarian Tumors and Serous Malignant Ovarian Tumors.

OBJECTIVE: To investigate whether multidetector computed tomography (MDCT)-based radiomics features can discriminate between serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs). PATIENTS AND METHODS: Eighty patients with SBOTs and 102 patients with SMOTs, confirmed by pathology (training set: n = 127; validation set: n = 55) from December 2017 to June 2020, were enrolled in this study. The interclass correlation coefficient (ICC) and least absolute shrinkage and selection operator (LASSO) regression were applied to select radiomics parameters derived from MDCT images on the arterial phase (AP), venous phase (VP), and equilibrium phase (EP). Receiver operating characteristic (ROC) analysis of each selected parameter was carried out. Heat maps were created to illustrate the distribution of the radiomics parameters. Three models incorporating selected radiomics parameters generated by support vector machine (SVM) classifiers in each phase were analyzed by ROC and compared using the DeLong test. RESULTS: The most predictive features selected by ICC and LASSO regression between SBOTs and SMOTs included 9 radiomics parameters on AP, VP, and EP each. Three models on AP, VP, and EP incorporating the selected features generated by SVM classifiers produced AUCs of 0.80 (accuracy, 0.75; sensitivity, 0.74; specificity, 0.75), 0.86 (accuracy, 0.78; sensitivity, 0.80; specificity, 0.75), and 0.73 (accuracy, 0.69; sensitivity, 0.71; specificity, 0.67), respectively. There were no significant differences in the AUCs among the three models (AP vs. VP, P = 0.199; AP vs. EP, P = 0.260; VP vs. EP, P = 0.793). CONCLUSION: MDCT-based radiomics features could be used as biomarkers for the differentiation of SBOTs and SMOTs.

MCM3AP-AS1/miR-876-5p/WNT5A axis regulates the proliferation of prostate cancer cells.

BACKGROUND: Although the fact that long non-coding RNA MCM3AP antisense RNA 1 (MCM3AP-AS1) is oncogenic in several cancers is well documented, very few researchers investigate its expression and function in prostate cancer. METHODS: Paired prostate cancer samples were selected, and expressions of MCM3AP-AS1, miR-876-5p and WNT5A were examined by qRT-PCR. MCM3AP-AS1 shRNA was transfected into LNCaP and PC-3 cell lines, and then the proliferative activity and apoptosis of cancer cells were detected by CCK-8 assay, EdU assay and flow cytometry analysis, respectively. qRT-PCR and Western blot were used to analyze the changes of miR-876-5p and WNT5A. Luciferase reporter gene assay was employed to determine the regulatory relationship between miR-876-5p and MCM3AP-AS1, miR-876-5p and WNT5A. RESULTS: MCM3AP-AS1 was significantly up-regulated in cancerous tissues of prostate cancer samples, positively correlated with the expression of WNT5A, while negatively related with miR-876-5p. After transfection of MCM3AP-AS1 shRNA into prostate cancer cells, the proliferative ability of cancer cells was signally inhibited, but the apoptosis of cancer cells was increased. MCM3AP-AS1 shRNA could reduce the expression of WNT5A on both mRNA and protein levels. Besides, MCM3AP-AS1 was identified as a sponge of miR-876-5p. WNT5A was validated as a target gene of miR- 876-5p. CONCLUSION: MCM3AP-AS1 is abnormally up-regulated in prostate cancer tissues and can modulate the proliferation and apoptosis of prostate cancer cells, which has the potential to be the "ceRNA" to regulate the expression of WNT5A by targeting miR-876-5p.

Circ_0000527 promotes the progression of retinoblastoma by regulating miR-646/LRP6 axis.

BACKGROUND: Researches validate that circular RNAs (circRNAs) are dysregulated in a variety of malignancies and play an important role in regulating the malignant phenotype of tumor cells. Nevertheless, the role of circ_0000527 in retinoblastoma (RB) and its regulatory mechanisms remain largely unknown. METHODS: Real-time PCR (RT-PCR) was used to detect circ_0000527 and miR-646 expression in RB tissues and cells. The LRP6 expression in RB cells was detected by Western blot. The relationship between circ_0000527 expression and the clinicopathological parameters of RB patients was analyzed. Cell proliferation, apoptosis and metastasis were monitored by cell counting kit-8 (CCK-8), flow cytometry, and Transwell assay. The dual-luciferase reporter gene assay and RIP assay were employed to verify the targeting relationship between circ_0000527 and miR-646, miR-646 and LRP6. RESULTS: Circ_0000527 was highly expressed in both RB and RB cell lines, whose high expression level and degree of differentiation were significantly correlated with the increase in cTNM staging level. Overexpression of circ_0000527 contributed to RB cell proliferation, migration, invasion and suppressed cell apoptosis, while knocking down circ_0000527 inhibited the above malignant biological behavior. The underlying mechanism suggested that functioning as a endogenous competitive RNA, circ_0000527 directly targeted miR-646 and positively regulated LRP6 expression. CONCLUSION: Circ_0000527 enhances the proliferation and metastasis of RB cells by modulating the miR-646/LRP6 axis.

Clinicopathologic features of the ureteral neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the ureter are extremely rare. There are only a few case reports in the past decades. Their clinicopathologic features, therapy and prognosis are not that clear. METHODS: 5 cases of ureteral neuroendocrine tumors were collected and reviewed of the literature. Histomorphology, immunophenotype and ultrastructural features were observed by HE, immunohistochemistry, special staining and electron microscopy. The clinical pathological data were retrospectively analyzed and followed up. RESULTS: Among the 5 patients, 1 was female and 4 were male, aged 62-82 years. 2 cases manifested intermittent hematuria, 1 had lower abdominal pain with frequent urination and dysuria, 1 with hydronephrosis, and 1 had no manifestations. All the 5 patients were treated with nephroureterectomy, 3 of which were also treated with excision of bladder cuff, 1 also had lymphadenectomy. On presentation, 2 cases in T2N0M0 (stage II), 2 cases in T3N0M0 (stage III), and 1case in T3N2M0 (stage IV). 2 cases were small cell neuroendocrine carcinoma, 1 was large cell neuroendocrine carcinoma and 2 were atypical carcinoid. The tumor cells were positive for neuroendocrine markers (CD56, CgA, Syn). 1 case of vimentin-positive small cell neuroendocrine carcinoma has a very good prognosis. Grimelius stain and electron microscopy observation showed numerous neuroendocrine granules in the cytoplasm. CONCLUSION: Ureteral neuroendocrine tumors are extremely rare. Neuroendocrine markers (CD56, CgA, Syn) and epithelial markers (CKpan, CK7) are usually helpful. Grimelius special staining and electron microscopy observation can help to make a final diagnosis. Radical surgery together with postoperative adjuvant chemotherapy can improve the survival of patients. Vimentin may play a role in predicting the prognosis.