Reduction in gefitinib resistance mediated by Yi-Fei San-Jie pill in non-small cell lung cancer through regulation of tyrosine metabolism, cell cycle, and the MET/EGFR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Yi-Fei San-Jie pill (YFSJ) has been used for adjuvant treatment in patients with lung cancer for a long time. AIM OF THE STUDY: Reports have indicated that the combination of gefitinib (Gef) with YFSJ inhibits the proliferation of EGFR-TKI-resistant cell lines by enhancing cellular apoptosis and autophagy in non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the effect of YFSJ on EGFR-TKI resistance and related metabolic pathways remain to be explored. MATERIALS AND METHODS: In our report, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), metabolomics, network pharmacology, bioinformatics, and biological analysis methods were used to investigate the mechanism. RESULTS: The UPLC-MS/MS data identified 42 active compounds of YFSJ extracts. YFSJ extracts can enhance the antitumor efficacy of Gef without hepatic and renal toxicity in vivo. The analysis of the metabolomics pathway enrichment revealed that YFSJ mainly affected the tyrosine metabolism pathway in rat models. Moreover, YFSJ has been shown to reverse Gef resistance and improve the effects of Gef on the cellular viability, migration capacity, and cell cycle arrest of NSCLC cell lines with EGFR mutations. The results of network pharmacology and molecular docking analyses revealed that tyrosine metabolism-related active compounds of YFSJ affect EGFR-TKIs resistance in NSCLC by targeting cell cycle and the MET/EGFR signaling pathway; these findings were validated by western blotting and immunohistochemistry. CONCLUSIONS: YFSJ inhibits NSCLC by inducing cell cycle arrest in the G1/S phase to suppress tumor growth, cell viability, and cell migration through synergistic effects with Gef via the tyrosine metabolic pathway and the EGFR/MET signaling pathway. To summarize, the findings of the current study indicate that YFSJ is a prospective complementary treatment for Gef-resistant NSCLC.

Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) has become one of the leading causes of disa-bility and death in diabetic patients. Restoring blood supply to the hindlimbs, especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. Tongxinluo (TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease. AIM: To investigate the effect of TXL on diabetic PAD and its underlying mechanisms. METHODS: An animal model of diabetic PAD was established by ligating the femoral artery of db/db mice. Laser Doppler imaging and micro-computed tomography (micro-CT) were performed to assess the recovery of blood flow and arteriogenesis. Endothelial cell function related to arteriogenesis and cellular pyroptosis was assessed using histopathology, Western blot analysis, enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction assays. In vitro, human vascular endothelial cells (HUVECs) and human vascular smooth muscle cells (VSMCs) were pretreated with TXL for 4 h, followed by incubation in high glucose and hypoxia conditions to induce cell injury. Then, indicators of HUVEC pyroptosis and function, HUVEC-VSMC interactions and the migration of VSMCs were measured. RESULTS: Laser Doppler imaging and micro-CT showed that TXL restored blood flow to the hindlimbs and enhanced arteriogenesis. TXL also inhibited endothelial cell pyroptosis via the reactive oxygen species/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3/Caspase-1/GSDMD signaling pathway. In addition, TXL restored endothelial cell functions, including maintaining the balance of vasodilation, acting as a barrier to reduce inflammation, and enhancing endothelial-smooth muscle cell interactions through the Jagged-1/Notch-1/ephrin-B2 signaling pathway. Similar results were observed in vitro. CONCLUSION: TXL has a pro-arteriogenic effect in the treatment of diabetic PAD, and the mechanism may be related to the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and promotion of endothelial cell-smooth muscle cell interactions.

Macrophages promote anti-androgen resistance in prostate cancer bone disease.

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Factors associated with gastrointestinal stromal tumor rupture and pathological risk: A single-center retrospective study.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare gastrointestinal mesenchymal tumor with potential malignancy. Once the tumor ruptures, regardless of tumor size and mitotic number, it can be identified into a high-risk group. It is of great significance for the diagnosis, treatment, and prognosis of GIST if non-invasive examination can be performed before surgery to accurately assess the risk of tumor. AIM: To identify the factors associated with GIST rupture and pathological risk. METHODS: A cohort of 50 patients with GISTs, as confirmed by postoperative pathology, was selected from our hospital. Clinicopathological and computed tomography data of the patients were collected. Logistic regression analysis was used to evaluate factors associated with GIST rupture and pathological risk grade. RESULTS: Pathological risk grade, tumor diameter, tumor morphology, internal necrosis, gas-liquid interface, and Ki-67 index exhibited significant associations with GIST rupture (P < 0.05). Gender, tumor diameter, tumor rupture, and Ki-67 index were found to be correlated with pathological risk grade of GIST (P < 0.05). Multifactorial logistic regression analysis revealed that male gender and tumor diameter ≥ 10 cm were independent predictors of a high pathological risk grade of GIST [odds ratio (OR) = 11.12, 95% confidence interval (95%CI): 1.81-68.52, P = 0.01; OR = 22.96, 95%CI: 2.19-240.93, P = 0.01]. Tumor diameter ≥ 10 cm, irregular shape, internal necrosis, gas-liquid interface, and Ki-67 index ≥ 10 were identified as independent predictors of a high risk of GIST rupture (OR = 9.67, 95%CI: 2.15-43.56, P = 0.01; OR = 35.44, 95%CI: 4.01-313.38, P < 0.01; OR = 18.75, 95%CI: 3.40-103.34, P < 0.01; OR = 27.00, 95%CI: 3.10-235.02, P < 0.01; OR = 4.43, 95%CI: 1.10-17.92, P = 0.04). CONCLUSION: Tumor diameter, tumor morphology, internal necrosis, gas-liquid, and Ki-67 index are associated with GIST rupture, while gender and tumor diameter are linked to the pathological risk of GIST. These findings contribute to our understanding of GIST and may inform non-invasive examination strategies and risk assessment for this condition.

Current Advances and Outlook in Gastric Cancer Chemoresistance: A Review.

BACKGROUND: Surgical resection of the lesion is the standard primary treatment of gastric cancer. Unfortunately, most patients are already in the advanced stage of the disease when they are diagnosed with gastric cancer. Alternative therapies, such as radiation therapy and chemotherapy, can achieve only very limited benefits. The emergence of cancer drug resistance has always been the major obstacle to the cure of tumors. The main goal of modern cancer pharmacology is to determine the underlying mechanism of anticancer drugs. OBJECTIVES: Here, we mainly review the latest research results related to the mechanism of chemotherapy resistance in gastric cancer, the application of natural products in overcoming the chemotherapy resistance of gastric cancer, and the new strategies currently being developed to treat tumors based on immunotherapy and gene therapy. CONCLUSION: The emergence of cancer drug resistance is the main obstacle in achieving alleviation and final cure for gastric cancer. Mixed therapies are considered to be a possible way to overcome chemoresistance. Natural products are the main resource for discovering new drugs specific for treating chemoresistance, and further research is needed to clarify the mechanism of natural product activity in patients.

Comprehensive analysis of an immune infiltrate-related competitive endogenous RNA network reveals potential prognostic biomarkers for non-small cell lung cancer.

Globally, non-small cell lung cancer (NSCLC) is the most common malignancy and its prognosis remains poor because of the lack of reliable early diagnostic biomarkers. The competitive endogenous RNA (ceRNA) network plays an important role in the tumorigenesis and prognosis of NSCLC. Tumor immune microenvironment (TIME) is valuable for predicting the response to immunotherapy and determining the prognosis of NSCLC patients. To understand the TIME-related ceRNA network, the RNA profiling datasets from the Genotype-Tissue Expression and The Cancer Genome Atlas databases were analyzed to identify the mRNAs, microRNAs, and lncRNAs associated with the differentially expressed genes. Weighted gene co-expression network analysis revealed that the brown module of mRNAs and the turquoise module of lncRNAs were the most important. Interactions among microRNAs, lncRNAs, and mRNAs were prognosticated using miRcode, miRDB, TargetScan, miRTarBase, and starBase databases. A prognostic model consisting of 13 mRNAs was established using univariate and multivariate Cox regression analyses and validated by the receiver operating characteristic (ROC) curve. The 22 immune infiltrating cell types were analyzed using the CIBERSORT algorithm, and results showed that the high-risk score of this model was related to poor prognosis and an immunosuppressive TIME. A lncRNA-miRNA-mRNA ceRNA network that included 69 differentially expressed lncRNAs (DElncRNAs) was constructed based on the five mRNAs obtained from the prognostic model. ROC survival analysis further showed that the seven DElncRNAs had a substantial prognostic value for the overall survival (OS) in NSCLC patients; the area under the curve was 0.65. In addition, the high-risk group showed drug resistance to several chemotherapeutic and targeted drugs including cisplatin, paclitaxel, docetaxel, gemcitabine, and gefitinib. The differential expression of five mRNAs and seven lncRNAs in the ceRNA network was supported by the results of the HPA database and RT-qPCR analyses. This comprehensive analysis of a ceRNA network identified a set of biomarkers for prognosis and TIME prediction in NSCLC.

Ginsenoside Rg3 Promotes Cell Growth Through Activation of mTORC1.

Ginsenoside Rg3 is a steroidal saponin isolated from Panax ginseng. Previous studies have shown that Rg3 treatment downregulates the activity of rapamycin complex 1 (mTORC1) activity and inhibits the growth of cancer cells. However, the inhibitory effect of Rg3 on cancer cells is associated with high concentrations of Rg3 that are difficult to achieve in vivo. The human cervix adenocarcinoma HeLa cells were treated with Rg3. The protein levels of AMP-activated protein kinase alpha (AMPKα), protein kinase B(Akt), ribosomal S6 protein(S6), and Erk were determined by immunoblotting analyses. We used a fluorescent probe to detect reactive oxygen species (ROS) production in living cells. The oxygen consumption rate (OCR) was examined by the Seahorse Extracellular Flux Analyzer. The content of adenosine triphosphate (ATP) was measured by ATPlite kit and Mitotracker was applied to detect the mitochondria. We showed that at lower concentrations, Rg3 activates mTORC1 independent of AKT and AMP-activated protein kinase (AMPK). Rg3 promotes mitochondrial biogenesis and function, increases the oxygen consumption of mitochondria and the content of ATP. This effect is in contrast to that of high concentrations of Rg3, which inhibits cell growth. These findings demonstrate a pro-growth activity of Rg3 that acts through mTORC1 and mitochondrial biogenesis and suggest a dose-dependent effect of Rg3 on tumor cell growth.

2+0 CYP21A2 deletion carrier - a limitation of the genetic testing and counseling: A case report.

BACKGROUND: CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity, leading to development of congenital adrenal hyperplasia (CAH) with different clinical phenotypes. For families with CAH children, genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence. CASE SUMMARY: We report a case of CAH with a high suspicion before delivery. The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results. Our report confirmed a CYP21A2 homozygous deletion in this case, CYP21A2 heterozygous deletion in the mother, and a rare 2+0 CYP21A2 deletion in the father. CONCLUSION: It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.

Giant cell tumors of the mobile spine with invasion of adjacent vertebrae: an unusual imaging finding.

BACKGROUND: Giant cell tumors of the mobile spine invasion of the adjacent vertebrae are an ignored imaging finding. METHODS: Nine patients with giant cell tumors of the mobile spine with invasion of the adjacent vertebrae confirmed by pathology were enrolled. Eight patients had pure giant cell tumors (GCTs), while one patient also had an aneurysmal bone cyst. All patients underwent conventional computed tomography, three-dimensional reconstruction, and conventional magnetic resonance imaging, while seven patients also underwent post-contrast magnetic resonance imaging. RESULTS: All patients showed GCTs of the mobile spine that arose from the vertebral body and extended to the vertebral arch. The tumors showed soft-tissue attenuation with no evidence of a mineralized matrix. Pathological fracture was seen in five patients. The margin of the original tumor showed partial sclerosis in four patients and involved an adjacent vertebral body with a sclerotic rim in two patients. The tumors showed a homogeneous and similar signal intensity to the normal spinal cord on T1WI (T1-weighted image) in five patients. The cystic area of the tumors was hyperintense on T2WI in the remaining four patients, while one patient showed hemorrhage that was hyperintense on T1WI. The solid components of the GCTs show marked enhancement in all cases, while the cystic area of the tumors was observed without enhancement on contrast-enhanced images in four patients. Bone destruction of the adjacent vertebral body showed a homogeneous signal on T1WI and T2WI and marked enhancement on contrast-enhanced images. CONCLUSIONS: Giant cell tumors of the mobile spine with invasion into adjacent vertebrae are an unusual imaging finding. Radiologists should be familiar with this imaging characteristic.

Extraosseous spinal epidural plasmocytoma associated with multiple myeloma: Two case reports.

BACKGROUND: Multiple myeloma is a malignant hematological disease characterized by proliferation of monoclonal plasma cells mainly in the bone marrow. Extraosseous epidural plasmacytoma associated with myeloma arises from lymphoid tissue in the epidural space without focal vertebral involvement, and is rare. CASE SUMMARY: A 52-year-old woman was diagnosed with kappa subtype nonsecretory multiple myeloma and presented with bilateral arm weakness 11 mo after completing multiple courses of chemotherapy. Spinal magnetic resonance imaging (MRI) showed a posterior C7-T3 epidural mass with spinal cord compression. After five courses of chemotherapy, follow-up MRI showed resolution of cord compression. A 54-year-old man presented with paraplegia 15 mo after a diagnosis of IgD kappa subtype multiple myeloma and completing multiple courses of chemotherapy. He underwent Th11 and L1 laminectomies for tumor resection because MRI showed an epidural mass causing cord compression. His-topathologic examination was consistent with IgD multiple myeloma. The patients have currently survived for 33 mo and 19 mo, respectively. CONCLUSION: Isolated extraosseous epidural plasmacytoma associated with multiple myeloma without bony involvement is difficult to diagnose by imaging. Definitive diagnosis requires pathological and immunohistochemical examination.

Adjuvant EGFR-TKIs for Patients With Resected EGFR-Mutant Non-Small Cell Lung Cancer: A Meta-Analysis of 1,283 Patients.

BACKGROUND: Cisplatin-based chemotherapy was previously considered as the standard adjuvant therapy for improved overall survival (OS) in patients with non-small cell lung cancer (NSCLC) after surgery. However, the benefit was limited due to high risks of recurrence and adverse events. In the present study, the efficacy of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for EGFR-mutant patients after surgery was investigated using the latest updated data. METHODS: This meta-analysis included a comprehensive range of relevant studies identified from database searches. Disease-free survival (DFS) and OS with hazard ratios (HRs) were calculated using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: A total of seven randomized clinical trials were included in the meta-analysis and involved 1,283 NSCLC patients harboring EGFR mutations. In resected EGFR-mutant NSCLC patients, adjuvant EGFR-TKIs were significantly better than chemotherapy in terms of DFS (HR: 0.41; 95%CI: 0.24-0.70, P = 0.001), without showing any benefit in OS (HR: 0.72; 95%CI: 0.37-1.41, P = 0.336). No significant difference in DFS was observed between patients with EGFR exon 19 deletion and those with L858R mutation. Resected EGFR-mutant NSCLC patients treated with osimertinib experienced improved DFS and a lower risk of brain recurrence than those treated with gefitinib or erlotinib. Adjuvant EGFR-TKIs reduced the risk of bone and lung relapse, without decreasing the risk of local recurrence and liver relapse. CONCLUSION: This meta-analysis shows that adjuvant EGFR-TKI therapy could significantly prolong DFS in patients with resected EGFR-mutant NSCLC. Treatment with osimertinib showed improved DFS with a lower risk of brain recurrence than treatment with gefitinib or erlotinib for resected disease.

TOR targets an RNA processing network to regulate facultative heterochromatin, developmental gene expression and cell proliferation.

Cell proliferation and differentiation require signalling pathways that enforce appropriate and timely gene expression. We find that Tor2, the catalytic subunit of the TORC1 complex in fission yeast, targets a conserved nuclear RNA elimination network, particularly the serine and proline-rich protein Pir1, to control gene expression through RNA decay and facultative heterochromatin assembly. Phosphorylation by Tor2 protects Pir1 from degradation by the ubiquitin-proteasome system involving the polyubiquitin Ubi4 stress-response protein and the Cul4-Ddb1 E3 ligase. This pathway suppresses widespread and untimely gene expression and is critical for sustaining cell proliferation. Moreover, we find that the dynamic nature of Tor2-mediated control of RNA elimination machinery defines gene expression patterns that coordinate fundamental chromosomal events during gametogenesis, such as meiotic double-strand-break formation and chromosome segregation. These findings have important implications for understanding how the TOR signalling pathway reprogrammes gene expression patterns and contributes to diseases such as cancer.

Reliability and Validity of Abdominal Skeletal Muscle Area Measurement Using Magnetic Resonance Imaging.

RATIONALE AND OBJECTIVES: Skeletal muscle mass measurement is the most important element for diagnosing sarcopenia. MRI has an excellent soft-tissue contrast, which can non-invasively assess abdominal skeletal muscle area (SMA) as well as CT. This study aimed to assess the validity and reliability of abdominal SMA measurement by comparing CT and MRI based on the fat image of IDEAL-IQ sequence at the lumbar level mid-L3. MATERIALS AND METHODS: CT and MRI images of 32 patients diagnosed with various kidney diseases were used to analyze intra-observer variability among abdominal SMA measurements. This was done to evaluate the correlation of SMA between CT and fat images of MRI. SMA images were segmented using Materialise Mimics software before quantification. Interobserver reliability and validation of measurements was evaluated by two independent investigators. Abdominal SMA reproducibility and correlation between CT and MRI were then assessed using the intraclass correlation coefficient (ICC), coefficient of variation (CV), Bland-Altman plot, and Pearson's correlation coefficient respectively. RESULTS: The interobserver reliability of MRI was excellent. The CV value was 2.82% while the ICC values ranged between 0.996 and 0.999. Validity was high (CV was 1.7% and ICC ranged between 0.986 and 0.996) for measurements by MRI and CT. Bland Altman analysis revealed an average difference of 2.2% between MRI and CT. The Pearson's correlation coefficient was 0.995 (p < 0.0001). This result revealed that there was a strong correlation between the two technologies. CONCLUSION: MRI exhibited good interobserver reliability and excellent agreement with CT for quantification of abdominal SMA.

Construction of a Prognostic Immune Signature for Squamous-Cell Lung Cancer to Predict Survival.

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs. Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles. Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort (n = 232) and the testing cohort (n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts (P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts. Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients.

Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy.

Macroautophagy (autophagy) is driven by the coordinated actions of core autophagy-related (Atg) proteins. Atg8, the core Atg protein generally considered acting most downstream, has recently been shown to interact with other core Atg proteins via their Atg8-family-interacting motifs (AIMs). However, the extent, functional consequence, and evolutionary conservation of such interactions remain inadequately understood. Here, we show that, in the fission yeast Schizosaccharomyces pombe, Atg38, a subunit of the phosphatidylinositol 3-kinase (PtdIns3K) complex I, interacts with Atg8 via an AIM, which is highly conserved in Atg38 proteins of fission yeast species, but not conserved in Atg38 proteins of other species. This interaction recruits Atg38 to Atg8 on the phagophore assembly site (PAS) and consequently enhances PAS accumulation of the PtdIns3K complex I and Atg proteins acting downstream of the PtdIns3K complex I, including Atg8. The disruption of the Atg38-Atg8 interaction leads to the reduction of autophagosome size and autophagic flux. Remarkably, the loss of this interaction can be compensated by an artificial Atg14-Atg8 interaction. Our findings demonstrate that the Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop between Atg8 and the PtdIns3K complex I to promote efficient autophagosome formation, underscore the prevalence and diversity of AIM-mediated connections within the autophagic machinery, and reveal unforeseen flexibility of such connections. Abbreviations: AIM: Atg8-family-interacting motif; AP-MS: affinity purification coupled with mass spectrometry; Atg: autophagy-related; FLIP: fluorescence loss in photobleaching; PAS: phagophore assembly site; PB: piggyBac; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate.

Modified Liujunzi Decoction () Alleviates Chemotherapy-Induced Anorexia in Advanced Non-Small Cell Lung Cancer: A Propensity Score Matched Case-Control Study.

OBJECTIVE: To evaluate the effect of Chinese herbal medicine formula, modified Liujunzi Decoction (, MLJZT), for anorexia, utilized as adjunct therapy during chemotherapy treatment for patients with advanced non-small cell lung cancer (NSCLC). METHODS: The study adopted a propensity score-matched design based on a prospective database. From February 2016 to September 2017, patients with advanced NSCLC that received both cisplatin-based chemotherapy and MLJZT (IM group) were 1:1 propensity score-matched to patients that received the cisplatin-based chemotherapy alone (control group). Changes in anorexia and weight, as well as side effects were evaluated per week within 4-cycle chemotherapy. RESULTS: Overall, 156 patients with advanced NSCLC that had received chemotherapy from our database were identified and 53 pairs were matched successfully. In total, 48.6% (50/53) of patients in the IM group had anorexia-improvement compared to 28.3% (15/53) of patients in the control group, and a total of 39.6% (21/53) of patients in the control group had a worsening of anorexia compared to only 7.8% (8/53) of patients in the IM group (P<0.01). The weight reduced significantly over time in the control group (-2.36 ± 2.53 kg) as compared to the IM group (-0.62 ± 3.89 kg, P<0.01). CHM didn't reduce the efficacy of chemotherapy in shrinking tumor size, and didn't increase the incidence of side effects such as hematological and hepatorenal toxicity. CONCLUSION: MLJZT is effective and safe for alleviating anorexia in patients with NSCLC. These findings warrant the conduct of a randomized controlled trial.

Rosmarinic acid reverses non-small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway.

Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC.

Corrigendum: Glucose-Regulated Protein 78 Signaling Regulates Hypoxia-Induced Epithelial-Mesenchymal Transition in A549 Cells.

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Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway.

Cisplatin (DDP) is the first-line chemotherapeutic agent against lung cancer. However, the therapeutic effect of DDP loses over time due to the acquired drug resistance in non-small cell lung cancer (NSCLC) cells. In recent years, the role of the traditional Chinese medicine (TCM) cordycepin (Cor) in cancer treatment has been attracting attention. However, the effects of Cor on DDP resistance in NSCLC are unclear. In the present study, we aimed to investigate the effects of Cor in combination with DDP on cell proliferation and apoptosis in NSCLC and explore possible underlying mechanisms. The cell proliferation and apoptosis were analyzed in NSCLC parental (A549) and DDP-resistant (A549DDP) cells treated with DDP alone or in combination with Cor both in vitro and in vivo. Different genes and signaling pathways were investigated between DDP-sensitive and DDP-resistant A549 cells by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The perturbations of the MAPK and PI3K-AKT signaling pathways were evaluated by Western blot analysis. Our data showed that Cor markedly enhanced DDP inhibition on cell proliferation and promotion of apoptosis compared to the DDP-alone group in both A549 and A549DDP cells. The synergic actions were associated with activation of AMPK; inhibition of AKT, mTOR, and downstream P709S6K; and S6 phosphorylation in the AKT pathway compared with DDP alone. Collectively, combination of Cor and DDP has a synergistic effect in inhibiting proliferation and promoting apoptosis of NSCLC cells in the presence or absence of DDP resistance. The antitumor activity is associated with activation of AMPK and inhibition of the AKT pathway to enhance DDP inhibition on NSCLC. Our results suggested that Cor in combination with DDP could be an additional therapeutic option for the treatment of DDP-resistant NSCLC.

Positioning Heterochromatin at the Nuclear Periphery Suppresses Histone Turnover to Promote Epigenetic Inheritance.

In eukaryotes, heterochromatin is generally located at the nuclear periphery. This study investigates the biological significance of perinuclear positioning for heterochromatin maintenance and gene silencing. We identify the nuclear rim protein Amo1NUPL2 as a factor required for the propagation of heterochromatin at endogenous and ectopic sites in the fission yeast genome. Amo1 associates with the Rix1PELP1-containing RNA processing complex RIXC and with the histone chaperone complex FACT. RIXC, which binds to heterochromatin protein Swi6HP1 across silenced chromosomal domains and to surrounding boundary elements, connects heterochromatin with Amo1 at the nuclear periphery. In turn, the Amo1-enriched subdomain is critical for Swi6 association with FACT that precludes histone turnover to promote gene silencing and preserve epigenetic stability of heterochromatin. In addition to uncovering conserved factors required for perinuclear positioning of heterochromatin, these analyses elucidate a mechanism by which a peripheral subdomain enforces stable gene repression and maintains heterochromatin in a heritable manner.