Hepatic cavernous hemangioma developed in non-small cell lung cancer patients after receiving Camrelizumab treatment: two case reports.

Purpose: To report two cases of hepatic cavernous hemangioma, a rare complication, in patients with locally advanced and advanced non-squamous non-small cell lung cancer (NSCLC) treated with PD-1 inhibitors. Additionally, to share clinical experiences related to the management of this condition. Methods: Two patients with locally advanced and advanced non-squamous non-small cell lung cancer (NSCLC) were enrolled in our hospital. Following the NCCN guidelines and expert consensus, both patients received standard treatment with Camrelizumab (PD-1 inhibitor). Subsequent abdominal CT scans revealed hepatic focal lesions that did not exhibit typical characteristics of metastatic tumors. Therefore, further systematic investigation was conducted to study the hepatic focal lesions. Results: (1) Ultrasound-guided percutaneous biopsy confirmed the diagnosis of hepatic cavernous hemangioma. A multidisciplinary consultation concluded that it was an adverse drug reaction to Camrelizumab. (2) Ten-gene testing for both patients did not reveal any driver gene mutations associated with lung cancer. Apart from the occurrence of hepatic cavernous hemangioma, there were no signs of disease progression or worsening. (3) Both patients had resolution of hepatic cavernous hemangioma after switching to alternative PD-1 inhibitors or discontinuing PD-1 inhibitor treatment. One patient experienced hemorrhage related to the hepatic hemangioma, which was managed with hemostasis and symptomatic treatment, resulting in improvement. (4) Clinical outcomes: The first patient achieved a progression-free survival (PFS) of 33 months in first-line treatment and had not reached the PFS endpoint in second-line treatment, with an overall survival exceeding 56 months. The second patient had not reached the PFS endpoint in first-line treatment, with an overall survival exceeding 31 months. Conclusion: Hepatic cavernous hemangioma is a rare and serious adverse reaction associated with PD-1 inhibitors. Camrelizumab may interact with the PD-1 molecule in a different manner compared to other PD-1 inhibitors, affecting the regulation of the VEGFR/ULBP2 signaling pathway. In future studies, next-generation sequencing may provide detailed molecular pathology information, which could help explain individual differences and provide a basis for the prevention or intervention of hepatic cavernous hemangioma.

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug-disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2-Cyt c-caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.

Association between GLS Gene Polymorphisms and the Susceptibility to Lung Cancer in the Chinese Han Population.

BACKGROUND: Lung cancer is one of the most serious malignant tumors endangering human health and life. This study focused on evaluating the association between single nucleotide polymorphisms (SNPs) of the glutaminase (GLS) and lung cancer susceptibility in the Chinese Han population. METHODS: A total of 684 lung cancer patients and 684 healthy individuals were enrolled. Five GLS SNPs (rs143584207 C/A, rs117985587 T/C, rs74271715 G/T, rs2355570 G/A, and rs6713444 A/G) were screened as candidate genetic loci. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the association between GLS SNPs and lung cancer susceptibility. False-positive report probability (FPRP) analysis further verified whether the positive results deserved attention. Finally, the multi-factor dimensionality reduction (MDR) method was applied to analyze the interactions between SNPs. RESULTS: The overall analysis revealed that GLS rs143584207 and rs6713444 were significantly associated with lung cancer susceptibility. The subgroup and clinical information analyses further revealed that GLS rs143584207 and rs6713444 could remarkably reduce lung cancer susceptibility in different subgroups (age >60, females, body mass index (BMI) <24, and lung adenocarcinoma). Rs143584207 could significantly reduce lung cancer susceptibility in non-smokers. Additionally, rs6713444 also had a protective effect on patients with advanced lung cancer. CONCLUSIONS: Our study indicated that GLS rs143584207 and rs6713444 could strikingly reduce lung cancer susceptibility in the Chinese Han population, which will give a new direction for the timely treatment of lung cancer.

uORF-Mediated Translational Regulation of ATF4 Serves as an Evolutionarily Conserved Mechanism Contributing to Non-Small-Cell Lung Cancer (NSCLC) and Stress Response.

Diseases and environmental stresses are two distinct challenges for virtually all living organisms. In light of evolution, cellular responses to diseases and stresses might share similar molecular mechanisms, but the detailed regulation pathway is not reported yet.We obtained the transcriptomes and translatomes from several NSCLC (non-small-cell lung cancer) patients as well as from different species under normal or stress conditions. We found that the translation level of gene ATF4 is remarkably enhanced in NSCLC due to the reduced number of ribosomes binding to its upstream open reading frames (uORFs). We also showed the evolutionary conservation of this uORF-ATF4 regulation in the stress response of other species. Molecular experiments showed that knockdown of ATF4 reduced the cell growth rate while overexpression of ATF4 enhanced cell growth, especially for the ATF4 allele with mutated uORFs. Population genetics analyses in multiple species verified that the mutations that abolish uATGs (start codon of uORFs) are highly deleterious, suggesting the functional importance of uORFs.Our study proposes an evolutionarily conserved pattern that enhances the ATF4 translation by uORFs upon stress or disease. We generalized the concept of cellular response to diseases and stresses. These two biological processes may share similar molecular mechanisms.

The influence of cross-regional medical treatment on total medical expenses, medical insurance payments, and out-of-pocket expenses of patients with malignant tumors in Chinese low-income areas.

BACKGROUND: In recent years, due to the increasing number of cross-regional medical patients, countries around the world have issued a series of policies or regulations to reduce their out-of-pocket burden. In this context, this study intended to explore the impact of the Spatio-temporal characteristics of cross-regional medical treatment on total medical expenses, medical insurance payments, and out-of-pocket expenses of patients with malignant tumors in low-income areas. METHODS: This study included 54,904 data of cross-provincial medical treatment of malignant tumor patients insured in Heilongjiang Province, China in 2020. Firstly, Microsoft Excel 2019 and ArcGIS 10.2 were applied to conduct a descriptive analysis of the Spatio-temporal characteristics of their cross-provincial medical treatment. Then, binary and multivariate logistic regression models were used to explore the specific impact of economic level and geographical distance of medical regions on total medical expenses, medical insurance payments, and out-of-pocket expenses. RESULTS: The number of cross-regional medical patients showed a gradual upward trend from February to December, and fell back in January. They were concentrated in regions with high economic level and short distance from the insured region, where were more likely to form the group with high out-of-pocket expenses (AOR = 3.620, P < 0.001; AOR = 1.882, P < 0.001). While this possibility in middle-distance medical regions were less (AOR = 0.545, P < 0.001). Afterwards, two sensitivity analysis methods showed that the results were robust. CONCLUSION: The number of cross-regional medical patients with malignant tumors in low-income areas is affected by seasonal factors, meanwhile, their total medical expenses, actual medical insurance payment levels, and out-of-pocket expenses are all affected by the economic level and geographical distance of medical regions. And the middle-distance medical regions may be the best choice for patients with planned cross-regional medical treatment. These provide some evidence for policymakers to improve the fairness and sustainability of medical security for cross-regional medical patients and reduce their direct economic burden of disease.

Arabidopsis WRKY71 regulates ethylene-mediated leaf senescence by directly activating EIN2, ORE1 and ACS2 genes.

Leaf senescence is a pivotal step in the last stage of the plant life cycle and is influenced by various external and endogenous cues. A series of reports have indicated the involvement of the WRKY transcription factors in regulating leaf senescence, but the molecular mechanisms and signaling pathways remain largely unclear. Here we provide evidence demonstrating that WRKY71 acts as a positive regulator of leaf senescence in Arabidopsis. WRKY71-1D, an overexpressor of WRKY71, exhibited early leaf senescence, while wrky71-1, the WRKY71 loss-of-function mutant, displayed delayed leaf senescence. Accordingly, a set of senescence-associated genes (SAGs) were substantially elevated in WRKY71-1D but markedly decreased in wrky71-1. Chromatin immunoprecipitation assays indicated that WRKY71 can bind directly to the promoters of SAG13 and SAG201. Transcriptome analysis suggested that WRKY71 might mediate multiple cues to accelerate leaf senescence, such as abiotic stresses, dark and ethylene. WRKY71 was ethylene inducible, and treatment with the ethylene precursor 1-amino-cyclopropane-1-carboxylic acid enhanced leaf senescence in WRKY71-1D but caused only a marginal delay in leaf senescence in wrky71-1. In vitro and in vivo assays demonstrated that WRKY71 can directly regulate ETHYLENE INSENSITIVE2 (EIN2) and ORESARA1 (ORE1), genes of the ethylene signaling pathway. Consistently, leaf senescence of WRKY71-1D was obviously retarded in the ein2-5 and nac2-1 mutants. Moreover, WRKY71 was also proved to interact with ACS2 in vitro and in vivo. Treatment with AgNO3 and aminoethoxyvinylglycine and acs2-1 could greatly arrest the leaf senescence of WRKY71-1D. In conclusion, our data revealed that WRKY71 mediates ethylene signaling and synthesis to hasten leaf senescence in Arabidopsis.

Tongmai Yangxin pill reduces myocardial No-reflow via endothelium-dependent NO-cGMP signaling by activation of the cAMP/PKA pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease. Previous studies have confirmed that TMYX can improve vascular endothelial function in patients with coronary heart disease by upregulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels. The underlying cAMP/PKA and NO-cGMP signaling pathway-dependent mechanism is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish the NR model. TMYX (4.0 g/kg) was orally administered throughout the experiment. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were used to evaluate the NR and ischemic areas. Pathological changes in the myocardium were assessed by hematoxylin-eosin staining. An automated biochemical analyzer and kit were used to detect the activities of myocardial enzymes and myocardial oxidants, including CK, CK-MB, LDH, reactive oxygen species, superoxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins related to the cAMP/PKA and NO/cGMP signaling pathways were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was used to detect coronary artery diastolic function in vitro. RESULTS: TMYX elevated the EF, FS, LVOT peak, LVPWd and LVPWs values, decreased the LVIDd, LVIDs, LV-mass, IVSd, and LV Vols values, demonstrating cardio-protective effects, and reduced the NR and ischemic areas. Pathological staining showed that TMYX could significantly reduce inflammatory cell number and interstitial edema. The activities of CK, LDH, and MDA were reduced, NO activity was increased, and oxidative stress was suppressed after treatment with TMYX. TMYX not only enhanced the expression of Gs-α, AC, PKA, and eNOS but also increased the expression of sGC and PKG. Furthermore, TMYX treatment significantly decreased ROCK expression. We further showed that TMYX (25-200 mg/mL) relaxed isolated coronary microvessels. CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the cAMP/PKA and NO/cGMP signaling pathways, further upregulating NO activity and relaxing coronary microvessels.

Tongmai Yangxin pill reduces myocardial no-reflow by regulating apoptosis and activating PI3K/Akt/eNOS pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty and was further improved by Professor Ruan Shiyi, a cardiovascular expert at Tianjin University of Traditional Chinese Medicine. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease and can improve vascular endothelial function in patients with angina pectoris or coronary heart disease by up-regulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial no-reflow by up-regulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by up-regulating NO activity and then dilating blood vessels. The mechanism underlying PI3K/Akt/eNOS pathway activation and apoptosis regulation is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish a NR model. The rats were assigned to 14 groups: control, sham, NR, TMYX (4.0 g/kg), sodium nitroprusside (SNP), Tongxinluo capsule (TXL), PI3K blocker (LY), TMYX + LY, SNP + LY, TXL + LY, eNOS blocker (L-NAME), TMYX + L-NAME, SNP + L-NAME, and TXL + L-NAME groups. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were adopted to evaluate NR and ischemic areas. Cell inflammation degree and edema were assessed by hematoxylin-eosin staining. Automated biochemical analyzer and kit were used to detect the activities of myocardial oxidants, including reactive oxygen species, super oxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins in the PI3K/Akt/eNOS signaling pathway and apoptosis were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was adopted to detect coronary artery diastolic function in vitro. RESULTS: TMYX reduced NR and ischemic areas; suppressed LV-mass; enhanced EF, FS, LVOT peak, and LVSV; and improved cardiac structure and function. Moreover, it decreased creatine kinase (CK), CK-MB, and lactic dehydrogenase activities. TMYX increased NO and super oxide dismutase activities; inhibited malonaldehyde activity; reduced muscle fiber swelling and inflammatory cell infiltration; and improved vasodilation in vitro. In the NR myocardium, TMYX stimulated myocardial PI3K activities and PI3K (Tyr458) phosphorylation and enhanced Akt activities and Akt phosphorylation at Tyr315. TMYX increased the activities of eNOS and the phosphorylation of eNOS at Ser1177 in the NR myocardium and attenuated cardiomyocyte apoptosis by increasing the expression of Bcl-2 and decreasing that of caspase-3 and Bax. All these effects of TMYX were abolished by the specific inhibitors of PI3K (LY) and eNOS (L-NAME). CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the PI3K/Akt/eNOS pathway and regulating apoptosis, further up-regulating NO activity and relaxing coronary microvessels.

A CT-based deep learning model for predicting the nuclear grade of clear cell renal cell carcinoma.

PURPOSE: To investigate the effects of different methodologies on the performance of deep learning (DL) model for differentiating high- from low-grade clear cell renal cell carcinoma (ccRCC). METHOD: Patients with pathologically proven ccRCC diagnosed between October 2009 and March 2019 were assigned to training or internal test dataset, and external test dataset was acquired from The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database. The effects of different methodologies on the performance of DL-model, including image cropping (IC), setting the attention level, selecting model complexity (MC), and applying transfer learning (TL), were compared using repeated measures analysis of variance (ANOVA) and receiver operating characteristic (ROC) curve analysis. The performance of DL-model was evaluated through accuracy and ROC analyses with internal and external tests. RESULTS: In this retrospective study, patients (n = 390) from one hospital were randomly assigned to training (n = 370) or internal test dataset (n = 20), and the other 20 patients from TCGA-KIRC database were assigned to external test dataset. IC, the attention level, MC, and TL had major effects on the performance of the DL-model. The DL-model based on the cropping of an image less than three times the tumor diameter, without attention, a simple model and the application of TL achieved the best performance in internal (ACC = 73.7 ±â€¯11.6%, AUC = 0.82 ±â€¯0.11) and external (ACC = 77.9 ±â€¯6.2%, AUC = 0.81 ±â€¯0.04) tests. CONCLUSIONS: CT-based DL model can be conveniently applied for grading ccRCC with simple IC in routine clinical practice.

CircRNA_100876 sponges miR-136 to promote proliferation and metastasis of gastric cancer by upregulating MIEN1 expression.

Previous reports have revealed that circRNA_100876 was extremely important in the progression of triple-negative breast cancer. Nevertheless, the mechanism towards the role of circRNA_100876 in Gastric cancer (GC) remains unknown. Here, we determined circRNA_100876 expression by quantitative real-time PCR (qRT-PCR) in twenty pairs of GC tissues and adjacent tissues. Our data indicated that the expression of circRNA_100876 was raised in GC tissues. In vitro, functional experiments confirmed that cell proliferation, invasion along with migration was promoted by circRNA_100876 in GC tissues. Simultaneously, relative luciferase assay uncovered that circRNA_100876 functioned as a sponge for miR-136, followed by retarding miR-136-induced inhibited effects on the corresponding target, MIEN1. Moreover, we revealed that the expression of MIEN1 was up-regulated and correlated to much worse prognosis of GC. Collectively, our data identified that the promotion of GC growth and metastasis induced by circRNA_100876 interacted with miR-136 and MIEN1, indicating an emerging announcement for uncovering the potential mechanism of GC progression.

Change of Pathological Type to Metaplastic Squamous Cell Carcinoma of the Breast During Disease Recurrence: Case Report and Literature Review.

Background: Metaplastic squamous cell carcinoma (SCC) of the breast is a rare and heterogeneous group of primary breast malignancies. The etiology, pathogenesis, and proper treatment for this kind rare breast cancer are still unclear. Case presentation: We reported a case of a 55-year-old woman with a palpable lump in the inner quadrant of the right breast. She underwent a right breast mass resection and sentinel lymph node biopsy, which revealed that the tumor was an invasive ductal carcinoma, followed by four cycles of doxorubicin plus cyclophosphamide and four cycles of docetaxel as adjuvant chemotherapy, and then simultaneous integrated boost intensity modulated radiotherapy to the whole right breast. After 2 years' follow-up, she had biopsy-proven disease recurrence in the right breast, which revealed SCC, and a mammogram showed abnormalities in the lower inner quadrant of the right breast and left axillary lymph nodes. Then we performed bilateral breast modified radical mastectomy, which confirmed that the recurrent tumors were metaplastic SCC, followed by adjuvant chemotherapy and adjuvant radiotherapy of the left supraclavicular and apical axillary regions. There has been no recurrent or metastatic evidence in the 16 months' follow-up since the second surgery. Conclusion: This case report shows that evolution of pathology type in recurrent breast cancer after initial treatment is possible. Detailed pathologic and immunohistochemical analyses are needed for identification of this change. Surgery and adjuvant radiation and chemotherapy are appropriate treatments for recurrent primary SCC of the breast.

Quercetin radiosensitizes non-small cell lung cancer cells through the regulation of miR-16-5p/WEE1 axis.

BACKGROUND: Quercetin, a widely distributed bioflavonoid, plays a role in combating diverse human cancers including non-small cell lung cancer (NSCLC). However, the role of quercetin in reversing the radioresistance of NSCLC cells and its underlying mechanism are far from being elucidated. METHOD: Radiation-resistant NSCLC cell lines were established. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of miR-16-5p and WEE1 G2 checkpoint kinase (WEE1) mRNA in radiation-resistant cells. After being treated with different concentrations of quercetin and different doses of X-ray, cell proliferation and apoptosis were monitored by CCK-8 assay, colony formation assay, and flow cytometry, respectively. Ultimately, the targeting relationship between miR-16-5p and WEE1 was verified via a dual fluorescent reporter gene assay. RESULTS: The expression of miR-16-5p was down-regulated in radiation-resistant cells, while the expression of WEE1 was up-regulated. Quercetin enhanced the radiosensitivity of NSCLC cells in a dose- and time-dependent manner. Furthermore, quercetin treatment increased the expression of miR-16-5p and decreased the expression of WEE1. The function of quercetin was reversed by miR-16-5p inhibitors or the transfection of WEE1 overexpressing plasmids. CONCLUSION: In conclusion, quercetin enhanced the radiosensitivity of NSCLC cells via modulating the expression of miR-16-5p and WEE1.

[Rosiglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice].

OBJECTIVE: To study the effect of rosiglitazone on atherosclerosis and potential mechanism in ApoE-knockout mice. METHODS: Thirty-two 6-week-old ApoE-knockout mice were used as atherosclerosis model in two groups: rosiglitazone group (n = 18) and control group (n = 14). Each group contained equal numbers of male and female mice. All mice were fed with normal chow diet. In addition to normal diet, rosiglitazone group received rosiglitazone 17 mg/kg of body weight/day. Venous bloods were collected for plasma glucose and lipid analysis, and aorta were prepared for morphologic and immunohistochemical analysis after 14 weeks. Aortic root (1 cm) was cut and prepared for paraffin slice. The histomorphometric analysis of atherosclerotic lesion was performed by means of HE; positive percentage of macrophage cell and tumor necrosis factor-alpha were measured by means of immunohistochemistry in cross section. The ratio of lesion/aortic wall surface in the rest aorta was measured by means of Sudan IV staining in longitudinal section. RESULTS: The amount of fatty streak in rosiglitazone group was significantly greater than that of control group; the gross number of lesions and the number of fibrous plaque and atheromatous plaque were similar in two groups. There were no differences in percentage of lesions in cross section in two groups. Rosiglitazone could significantly reduce the extend of atherosclerosis of longitudinal section, decrease the amount of macrophage cell and the level of tumor necrosis factor-alpha in lesions. The plasma glucose was normal and similar in two groups, and total cholesterol, LDL-cholesterol and triglyceride were significantly higher in rosiglitazone group. CONCLUSION: Rosiglitazone suppresses the expression of tumor necrosis factor-alpha, reduces the number of macrophage cell in lesion, and inhibits the development of atherosclerosis.