Subarachnoid hemorrhage with Takotsubo syndrome as the prominent manifestation: A case and literature review.

Background: Takotsubo syndrome, which is often induced by physical or psychological stress, is typically a cardiac syndrome with transient left ventricular dysfunction in the absence of obstructive coronary artery disease. Subarachnoid hemorrhage with typical symptoms and signs is frequently reported, whereas the incidence of subarachnoid hemorrhage with Takotsubo syndrome as the prominent manifestation without a typical headache is rarely reported. Case description: We present a rare case of a 63-year-old male patient with cough and fever as the first manifestations, accompanied by mild dizziness, headache, and mental discomfort; however, the patient was eventually diagnosed with atypical subarachnoid hemorrhage with Takotsubo syndrome. The patient underwent general anesthesia downwards stent-assisted spring coil embolization and was discharged from the hospital after postoperative treatment consisting of anti-cerebrovascular spasm, anti-platelet aggregation, and cerebrospinal fluid replacement. Conclusion: This case demonstrates the association between Takotsubo syndrome and subarachnoid hemorrhage. When patients present with unexplained pulmonary edema with mild neurologic symptoms, clinicians should be alerted to subarachnoid hemorrhage and Takotsubo syndrome.

Anlotinib Inhibits Cisplatin Resistance in Non-Small-Cell Lung Cancer Cells by Inhibiting MCL-1 Expression via MET/STAT3/Akt Pathway.

Background: Anlotinib is an effective targeted therapy for advanced non-small-cell lung cancer (NSCLC) and has been found to mediate chemoresistance in many cancers. However, the underlying molecular mechanism of anlotinib mediates cisplatin (DDP) resistance in NSCLC remains unclear. Methods: Cell viability was assessed by the cell counting kit 8 assay. Cell proliferation, migration, and invasion were determined using the colony formation assay and transwell assay. The mRNA expression levels of mesenchymal-epithelial transition factor (MET) and myeloid cell leukemia-1 (MCL-1) were measured by quantitative real-time PCR. Protein expression levels of MET, MCL-1, and STAT3/Akt pathway-related markers were examined using western blot analysis. Results: Our data showed that anlotinib inhibited the DDP resistance of NSCLC cells by regulating cell proliferation and metastasis. Moreover, MET and MCL-1 expression could be decreased by anlotinib treatment. Silencing of MET suppressed the activity of the STAT3/Akt pathway and MCL-1 expression. Furthermore, MET overexpression reversed the inhibitory effect of anlotinib on the DDP resistance of NSCLC cells, and this effect could be eliminated by MCL-1 knockdown or ACT001 (an inhibitor for STAT3/Akt pathway). Conclusion: Our results confirmed that anlotinib inhibited DDP resistance in NSCLC cells, which might decrease MCL-1 expression via mediating the MET/STAT3/Akt pathway.

Development and Validation of a Prediction Model of the Risk of Pneumonia in Patients with SARS-CoV-2 Infection.

Objective: To establish a prediction model of pneumonia risk in SARS-CoV-2-infected patients to reduce unnecessary chest CT scans. Materials and Methods: The model was constructed based on a retrospective cohort study. We selected SARS-CoV-2 test-positive patients and collected their clinical data and chest CT images from the outpatient and emergency departments of Hunan Provincial People's Hospital, China. Univariate and multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were utilized to identify predictors of pneumonia risk for patients infected with SARS-CoV-2. These predictors were then incorporated into a nomogram to establish the model. To ensure its performance, the model was evaluated from the aspects of discrimination, calibration, and clinical validity. In addition, a smoothed curve was fitted using a generalized additive model (GAM) to explore the association between the pneumonia grade and the model's predicted probability of pneumonia. Results: We selected 299 SARS-CoV-2 test-positive patients, of whom 205 cases were in the training cohort and 94 cases were in the validation cohort. Age, CRP natural log-transformed value (InCRP), and monocyte percentage (%Mon) were found to be valid predictors of pneumonia risk. This predictive model achieved good discrimination of AUC in the training and validation cohorts which was 0.7820 (95% CI: 0.7254-0.8439) and 0.8432 (95% CI: 0.7588-0.9151), respectively. At the cut-off value of 0.5, it had a sensitivity and specificity of 70.75% and 66.33% in the training cohort and 76.09% and 73.91% in the validation cohort, respectively. With suitable calibration accuracy shown in calibration curves, decision curve analysis indicated high clinical value in predicting pneumonia probability in SARS-CoV-2-infected patients. The probability of pneumonia predicted by the model was positively correlated with the actual pneumonia classification. Conclusion: This study has developed a pneumonia risk prediction model that can be utilized for diagnostic purposes in predicting the probability of pneumonia in patients infected with SARS-CoV-2.

METTL3 Promotes Endothelium-Mesenchymal Transition of Pulmonary Artery Endothelial Cells by Regulating TRPC6/Calcineurin/NFAT Signaling Pathways.

Background: Endothelium-mesenchymal transition (EndMT) is a process of phenotypic and functional transition from activated endothelial cells to mesenchymal cells. Recently, EndMT has been proved to be one of the main pathological mechanisms of pulmonary artery hypertension (PAH). However, the molecular mechanism is not clear. Methods: Primary rat pulmonary arterial endothelial cells (rPAECs) were isolated from Sprague-Dawley rats and verified by CD31 immunofluorescence staining. rPAECs were exposed to hypoxic conditions to induce EndMT. RNA and protein levels in cells were detected by RT-qPCR and Western blot. The migration ability was verified by the transwell assay. The RIP experiment was used to test the m6A modification of TRPC6 mRNA and the binding relationship between TRPC6 and METTL3. Calcineurin/NFAT signaling was measured by using commercial kits. Results: METTL3 was found to be highly expressed by hypoxia treatment in a time-dependent manner. Knockdown of METTL3 significantly suppressed cell migration, downregulated the levels of interstitial cell-related markers like α-SMA and vimentin, and increased the levels of endothelial cell markers including CD31 and VE-cadherin. Mechanistically, METTL3 increased TRPC6 expression by enhancing the m6A modification of TRPC6 mRNA, thus activating calcineurin/NFAT signaling. Our experiments showed that METTL3 silencing mediated the inhibitory roles in the hypoxia-mediated EndMT process, which were significantly reversed by TRPC6/calcineurin/NFAT signaling activation. Conclusion: Our results elucidated that METTL3 knockdown inhibited the hypoxia-mediated EndMT process by inactivating TRPC6/calcineurin/NFAT signaling.

A multidimensional model incorporating radiomics score and liquid biopsy for the prediction of malignant and benign pulmonary nodules.

Background: As the lesions in pulmonary nodules (PNs) are small and the clinical manifestations lack specificity, the etiology of PNs is complex, predisposing them to misdiagnoses missed diagnoses. Thus, the diagnosis and treatment of PNs remains challenging and an important clinical problem. Methods: This study prospectively enrolled 156 patients with computed tomography (CT)-diagnosed PNs who underwent circulating genetically abnormal cell (CAC) testing between January 2020 and December 2021. We collected data on clinical features closely related to the nature of PNs, such as age, smoking history, and type of nodule. All internal regions of interest (ROIs) of PNs in this study were segmented. Radiomic feature extraction was performed on the ROIs, and a radiomics model was constructed using least absolute shrinkage and selection operator (LASSO) regression to obtain a radiomics score (Rad-score). A comprehensive model combining clinical features, Rad-score, and liquid biopsy was constructed using logistic regression analysis. The diagnostic performance of the model was evaluated using receiver operating characteristic (ROC) curves. Results: In this study, 5 radiomics features were screened for model construction. The area under the ROC curve (AUC) of the radiomics model was 0.844 [95% confidence interval (CI): 0.766-0.915] in the training set. The Rad-score, clinical features, and CAC were further combined to construct a multidimensional analysis model. The AUC of the synthesized model was 0.943 (95% CI: 0.881-0.978) in the training set. Conclusions: A multidimensional model is an effective tool for the noninvasive diagnosis of malignant PNs. The validation and combination of multiple diagnostic methods is a productive avenue of research trend for the identification of malignant PNs.

Treatment outcome and prognostic analysis of advanced large cell neuroendocrine carcinoma of the lung.

The optimal systemic treatment of advanced large cell neuroendocrine carcinoma (LCNEC) is still controversial. We intend to explore advanced LCNEC through SEER database, construct nomogram model of advanced LCNEC, and understand the effect of different treatment regimens on LCNEC. We collected 909 patients, divided them into a training set validation set, constructed nomograms using Cox proportional hazards regression models, and evaluated nomogram discrimination and calibration by C-index and calibration curves. Kaplan-Meier will also be used to compare OS in different groups of patients and to explore the impact of different treatment regimens on advanced LCNEC. On the nomogram plotted, the nomogram predicted AUC values over time were always greater than 0.7, the C-index was 0.681 (95% CI 0.656-0.706) and 0.663 (95% CI 0.628-0.698) in the training and validation sets, respectively, and patients were divided into two groups according to risk, and a significant difference in OS was observed between the high-risk and low-risk groups in the training and validation cohorts. Different treatment analyses showed that chemotherapy is still the best treatment for advanced LCNEC. This nomogram provides a convenient and reliable tool for individual assessment and clinical decision-making of patients with advanced LCNEC.

Curcumin Increased the Sensitivity of Non-Small-Cell Lung Cancer to Cisplatin through the Endoplasmic Reticulum Stress Pathway.

Objective: Non-small-cell lung cancer (NSCLC) is one of the most lethal cancers. Although cisplatin-based chemotherapies have been regarded as a promising treatment approach, cisplatin resistance still remains one of the major clinical challenges. Curcumin, a naturally occurring polyphenol, has been proved to increase chemotherapeutic efficiency of NSCLC cells. However, the role of curcumin in cisplatin-resistant NSCLC cells has been rarely investigated. This study aims to investigate whether curcumin enhances cisplatin sensitivity of human NSCLC cells and its underlying mechanisms. Method: A549/DDP and H1299/DDP cells were treated by DDP or/and curcumin before cell viability, and apoptosis were determined by using a CCK-8 assay and flow cytometer. The expressions of apoptosis and ER stress-related proteins, including cleaved caspase-3, cleaved PARP, CHOP, GRP78, XBP-1, ATF6, and caspase-4, were measured by the qPCR and western blotting. After cotreatment by DDP and curcumin, A549/DDP and H1299/DDP cells were further treated by the ER stress inhibitor, salubrinal (20 µm), after which the cell apoptosis and viability were detected. Result: Treatment by DDP and curcumin can substantially decrease cell viability, while can increase the cell apoptosis rate, elevate mRNA and protein expressions of apoptosis and ER stress-related proteins, compared with cells treated by DDP or curcumin alone. Salubrinal treatment can counteract the suppressive effect of DDP and curcumin on cell viability and decrease the cell apoptosis of A549/DDP and H1299/DDP cells. Conclusion: Curcumin can increase the sensitivity of NSCLC to cisplatin through an ER stress pathway and thus can be served as one of the molecular targets for overcoming the cisplatin resistance.

A Red-Emitting COF Ionic Exchanged With Green-Emitting Tb(III) Complex Anion: Synthesis, Characterization, Ratiometric Emission Sensing, and Removal of Picric Acid.

Picric acid (PA) is an important chemical product which has been widely used in dye manufacturing, antiseptics, and pharmaceuticals. Owing to PA's extreme electron-deficient structure, its natural degradation is hard, leading to accumulation in the environment and finally threatening the ecosystem and human health. In this case, PA detection and removal becomes more and more important, concerning environmental protection and human health. In this study, an ionic covalent organic framework (I-COF) was synthesized and modified with a luminescent Tb(III) emitter (Tb(DPA)3 3-, DPA = pyridine-2,6-dicarboxylic acid), via ionic exchange. The resulting composite material (Tb-COF) was fully characterized by geometric analysis, IR, XRD, porosity analysis, SEM/TEM, and elemental analysis. It was found that Tb(DPA)3 3- was loaded into the hexagonal cage in an I-COF host with an ionic exchange ratio of 41%. The as-synthesized Tb-COF showed weak Tb(III) emission and strong red COF emission, after adding PA, Tb(III) emission was increased whereas COF emission weakened greatly, showing sensing behavior. Linear working curves were observed with good selectivity. The sensing mechanism was revealed as follows. PA molecules replaced the [Tb(PDA)3]3- component trapped in Tb-COF, releasing free luminescent [Tb(PDA)3]3-. After incorporating PA in the hexagonal cage, the COF emission was quenched. This sensing mechanism ensured a good selectivity over competing species, including cations, anions, and nitrocompounds. The adsorption and removal performance of I-COF for PA were investigated as well.

A Series of Photosensitizes for Fe3+ in Aqueous Solution and Cells With Colorimetric and Fluorescent Channels: Synthesis and Performance.

Ferrum (Fe) is a widely existing metal element and nearly the most important trace element in living species, including human beings. The design of chemosensors for Fe ions faces issues related to the d-d transition of Fe(II) and Fe(III) ions, which makes them efficient electron trappers and energy quenchers. Most fluorescent dyes cannot afford such d-d quenching, showing emission turn off effect towards both Fe(II) and Fe(III) ions with poor selectivity. As a consequence, the development for Fe with emission turn on effect and good selectivity shall be continued and updated. In this work, three rhodamine-derived chemosensors modified by different lengths of alkyl chains having electron-donating N and O atoms were synthesized and explored for the selective optical sensing of Fe(III). These chemosensors showed colorimetric and fluorescent emission turn on sensing for Fe(III), showing two sensing channels. These chemosensors showed good selectivity, which was assigned to the sieving effect of alkyl chains with electron-donating N and O atoms. The N atom was found to be more effective in associating with Fe(III), compared to the O atom. Their fluorescent cell imaging experiment was carried out to confirm the possibility of being used for cell imaging.

Hypoxia Upregulates NOTCH3 Signaling Pathway to Promote Endothelial-Mesenchymal Transition in Pulmonary Artery Endothelial Cells.

BACKGROUND: To investigate the effect of hypoxia on pulmonary artery endothelial cells and the role of NOTCH3 in endothelial-mesenchymal transition (EnMT) and to provide a research model for pulmonary disease and explain the pathogenesis of the pulmonary disease. METHODS: Pulmonary artery endothelial cells were divided into two groups and cultured in normoxic and hypoxic environments, respectively. QPCR, western blot, and immunofluorescence were used to detect endothelial cell-specific marker protein and mRNA expression in each group, and the ability of endothelial cells migration was evaluated by scratch and transwell experiment. RESULTS: The pulmonary artery endothelial cells in the normoxic group presented a typical pebble-like arrangement, and the endothelial cells in hypoxic culture showed a long spindle appearance. Hypoxia induced high expression of NOTCH3, Jagged-1, Hes1, c-Src, and CSL. Immunofluorescence showed that endothelial cells in hypoxic culture began to express the α-SMA, and the expression of vWF increased with hypoxia. Cell viability, scratch, and transwell results showed that endothelial cells in the hypoxic group were more capable of viability and migration than those in the normoxic group. The induction of EnMT by hypoxia can be inhibited by using notch3-specific inhibitor DAPT and Jagged-1. This study also found that miR-7-5p can regulate endothelial NOTCH3, indicating that miRNA is also involved in the process of endothelial-mesenchymal transformation. CONCLUSION: Hypoxia promotes the transformation of endothelial cells into mesenchymal cells by opening the NOTCH3 pathway, which lays the foundation for disease progression or clinical prognosis, and is of great significance in the treatment of diseases.

Good's syndrome with diffuse panbronchiolitis as the prominent manifestation: A case and literature review.

Good's syndrome (GS) is characterized by thymoma combined with adult-onset immunodeficiency. Diffuse panbronchiolitis (DPB) is a chronic inflammatory airway disease, which predominantly affects East Asians. Japanese scholars have reported extensively about GS combined with DPB or DPB-like pulmonary manifestation. However, such reports are rare in China. We report here a case of GS in China with DPB as the prominent manifestation and carry out a literature review accordingly. Our review indicates that in adults with DPB-like clinical manifestations, thymic lesions should be excluded and related immune function tests should be performed to exclude GS to avoid missed diagnosis and misdiagnosis.

CHOP overexpression sensitizes human non-small cell lung cancer cells to cisplatin treatment by Bcl-2/JNK pathway.

C/EBP homologous protein (CHOP), a 29 kDa cellular protein, plays a role in regulating tumor proliferation, differentiation, metabolism, cell death, and in tumor resistance to chemotherapy. Non-small cell lung cancer (NSCLC) is a tumor of the respiratory system and drug resistance is prevalent among NSCLC clinical cell cultures. Herein, our study elucidated the effect of CHOP on NSCLC cells with cisplatin resistance and its mechanism. In a NSCLC cell line with cisplatin-resistance, CHOP expression was decreased, compared with A549 cells. Overexpression of CHOP decreased the cell viability and enhanced cell apoptosis in the cells treated with cisplatin. Expression of CHOP also inhibited the cell proliferation and metastasis. CHOP increased the therapeutic effect of cisplatin on NSCLC cells through the Bcl-2/JNK pathway. In summary, CHOP regulated cisplatin resistance in cells of NSCLC by promoting the expression of apoptotic proteins and inhibiting the Bcl-2/JNK signaling pathway, indicating the antitumor effects of CHOP.

The methylation profiles of PRDM promoters in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading malignant tumors worldwide. Aberrant gene promoter methylation contributes to NSCLC, and PRDM is a tumor suppressor gene family that possesses histone methyltransferase activity. This study aimed to investigate whether aberrant methylation of PRDM promoter is involved in NSCLC. MATERIALS AND METHODS: Primary tumor tissues, adjacent nontumorous tissues, and distant lung tissues were collected from 75 NSCLC patients including 52 lung squamous cell carcinoma (LSCC) patients and 23 lung adenocarcinoma patients. The expression of PRDMs was detected by polymerase chain reaction (PCR), Western blot, and immunohistochemical analysis. The methylation of PRDM promoters was detected by methylation-specific PCR. The correlation of methylation and expression of PRDMs with clinicopathological characteristics of patients were analyzed. RESULTS: mRNA expression of PRDM2, PRDM5, and PRDM16 was low or absent in tumor tissues compared to distant lung tissues. The methylation frequencies of PRDM2, PRDM5, and PRDM16 in tumor tissues were significantly higher than those in distal lung tissues. In LSCC patients, methylation of PRDM2 and PRDM16 was correlated with smoking status and methylation of PRDM5 was correlated with tumor differentiation. CONCLUSION: The expression of PRDM2, PRDM5, and PRDM16 is low or absent in NSCLC, and this is mainly due to gene promoter methylation. Smoking may be an important cause of PRDM2 and PRDM16 methylation in NSCLC.

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract.

BACKGROUND/AIMS: Cigarette smoking is a major risk factor of chronic obstructive pulmonary disease. This study aimed to examine the effects of cigarette smoke extract (CSE) on alveolar type II epithelial cells (AECII) and investigate the underlying mechanism. METHODS: Primary AECII were isolated from rat lung tissues and exposed to CSE. Apoptosis was detected by flow cytometry. Protein expression was detected by Western blot analysis. RESULTS: Primary rat AECII maintained morphological and physiological characteristic after 3 passages. CSE increased the expression of ER specific pro-apoptosis factors CHOP and caspase 12, and the phosphorylation of JNK in AECII. CSE activated ER stress signaling and increased the phosphorylation of PERK, eIF2α and IRE1. Furthermore, CSE induced the expression of Hrd1, a key factor of ER-associated degradation, in AECII. Knockdown of Hrd1 led to more than 2 fold increase of apoptosis, while overexpression of Hrd1 attenuated CSE induced apoptosis of AECII. CONCLUSIONS: Our results suggest that ER stress induces HRD1 to protect alveolar type II epithelial cells from apoptosis induced by CSE.

Bevacizumab induces A549 cell apoptosis through the mechanism of endoplasmic reticulum stress in vitro.

AIMS: To observe the effect of bevacizumab on human A549 cells and explore its mechanism. METHODS: After different concentrations (0 µM, 1 µM, 5 µM, 25 µM) of bevacizumab treating in A549 cells, CCK8 assay detect the impact of bevacizumab on A549 cell proliferation and flow cytometry determine the effect of bevacizumab on human A549 cells apoptosis. Real-time PCR and Western blotting detect the changing expression of the target gene (CHOP, caspase-4, IRE1, XBP-1) on mRNA and Protein level. RESULTS: Treatment with bevacizumab for 24-hr have induced cell death in a does-dependent manner dramatically (P<0.05). In terms of the mRNA level, expression of XBP-1 has increased obviously in each group (1 µM, 5 µM, 25 µM) (P<0.01); the expression of CHOP (25 µM) and caspase-4 (5 µM) have increased slightly (P<0.05). In terms of the protein level, the expression of CHOP has increased obviously in each group (1 µM, 5 µM, 25 µM) when compared with the control group (0 µM) (P<0.05). As for caspase-4 (5 µM, 25 µM), the expression have increased slightly when compared with the control group (0 µM) (P<0.05). CONCLUSION: Bevacizumab can induce A549 cell apoptosis through the mechanism of endoplasmic reticulum stress.