Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

G3BP1 Interact with JAK2 mRNA to Promote the Malignant Progression of Nasopharyngeal Carcinoma via Activating JAK2/STAT3 Signaling Pathway.

Ras-GTPase-activating protein (GAP)-binding protein 1 (G3BP1) is an RNA-binding protein implicated in various malignancies. However, its role in nasopharyngeal carcinoma (NPC) remains elusive. This study elucidates the potential regulation mechanisms of G3BP1 and its significance in NPC advancement. Through knockdown and overexpression approaches, we validate G3BP1's oncogenic role by promoting proliferation, migration, and invasion in vitro and in vivo. Moreover, G3BP1 emerges as a key regulator of the JAK2/STAT3 signaling pathway, augmenting JAK2 expression via mRNA binding. Notably, epigallocatechin gallate (EGCG), a green tea-derived antioxidant, counteracts G3BP1-mediated pathway activation. Clinical analysis reveals heightened G3BP1, JAK2, and p-STAT3 as powerful prognostic markers, with G3BP1's expression standing as an independent indicator of poorer outcomes for NPC patients. In conclusion, the study unveils the oncogenic prowess of G3BP1, its orchestration of the JAK2/STAT3 signaling pathway, and its pivotal role in NPC progression.

Somatostatin receptor2 (SSTR2) expression, prognostic implications, modifications and potential therapeutic strategies associates with head and neck squamous cell carcinomas.

Head and neck squamous cell carcinomas (HNSCC) constitute a heterogeneous cluster of tumors celebrated for their predisposition to metastasize and exhibit local recurrence. Recent explorations have illuminated the intricate involvement of Somatostatin Receptor 2 (SSTR2), a growth-regulatory receptor traditionally classified as a tumor suppressor, yet concurrently implicated in bolstering specific tumor phenotypes. Advances in the realm of SSTR2 investigation within HNSCC, with a specific spotlight on laryngeal squamous cell carcinomas (LSCC), tongue squamous cell carcinomas (TSCC), and nasopharyngeal carcinomas (NPC), have been established. This study aims to provide a comprehensive overview of SSTR2 expression patterns, prognostic implications, distinctive signaling pathways, epigenetic modifications, and potential therapeutic strategies associated with SSTR2 in HNSCC.

Suppression of the SLC7A11/glutathione axis causes ferroptosis and apoptosis and alters the mitogen-activated protein kinase pathway in nasopharyngeal carcinoma.

SLC7A11 is a unit of the glutamate cystine antiporter Xc- system. It functions to import cystine for glutathione biosynthesis and maintains the redox balance in cells. Sorafenib inhibits the transporter activity of SLC7A11. The use of sorafenib has been approved in the treatment of multiple cancers. However, at present, our understanding of the mechanism of SLC7A11 and sorafenib in nasopharyngeal carcinoma (NPC) remains limited. We found that the expression of SLC7A11 was upregulated in NPC. A high SLC7A11 expression was associated with poor prognosis, metastasis, and an advanced T stage, which can be used as an independent prognostic indicator of NPC. In vitro, we observed that NPC cells relied on cystine for survival. Targeting SLC7A11 resulted in glutathione biosynthesis limitation, intracellular reactive oxygen species accumulation, lipid peroxides, ferroptosis, and apoptosis. Meanwhile, it altered mitogen activated protein kinase pathway, including p38 activation but ERK inhibition in NPC. This limited the proliferation of NPC cells. Sorafenib inhibited the proliferation and induced the death of NPC cells in vivo. In conclusion, SLC7A11 plays an important role in the occurrence and progression of NPC and may be a novel target for NPC treatment.

The complementary roles of STAT3 and STAT1 in cancer biology: insights into tumor pathogenesis and therapeutic strategies.

STATs are a family of transcription factors that regulate many critical cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of STATs is frequently observed in tumors and can directly drive cancer pathogenesis. STAT1 and STAT3 are generally viewed as mediating opposite roles in cancer development, with STAT1 suppressing tumorigenesis and STAT3 promoting oncogenesis. In this review, we investigate the specific roles of STAT1 and STAT3 in normal physiology and cancer biology, explore their interactions with each other, and offer insights into therapeutic strategies through modulating their transcriptional activity.

SSTR2 positively associates with EGFR and predicts poor prognosis in nasopharyngeal carcinoma.

AIMS: Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinases family and overexpression of EGFR has been linked to poor prognosis and cancer progression. Somatostatin receptor 2 (SSTR2) is a G-protein-coupled receptor (GPCR) with diverse biological functions in humans, and it is upregulated through the NF-KB signalling pathway in nasopharyngeal carcinomas (NPC). However, no studies have examined the EGFR and SSTR2 in NPC. This study aimed to investigate whether SSTR2 is associated with EGFR and clinicopathological features in NPC. METHODS: Bioinformatics analysis was performed to assess the correlation between EGFR and SSTR2 based on the GEO database. The expression of SSTR2 and EGFR was evaluated by immunohistochemistry (IHC) in 491 cases of NPC and 50 cases of non-cancerous nasopharyngeal epithelium. RESULTS: The bioinformatics analysis and IHC showed a positive correlation between SSTR2 and EGFR in NPC. High expression of SSTR2 and EGFR was significantly increased in NPC patients compared with non-cancerous nasopharyngeal epithelium. High expression of SSTR2 and/or EGFR was associated with a worse outcome and a higher risk of progression. The study found that patients receiving chemoradiotherapy (CR) with high expression of SSTR2, high expression of EGFR, and high coexpression of SSTR2 and EGFR had a poorer prognosis in both progression-free survival (PFS) and overall survival (OS). Interestingly, NPC patients with high expression of SSTR2, high expression of EGFR, high coexpression of EGFR and SSTR2, and EGFR/SSTR2 anyone high expression had a better prognosis with CR combined with targeted therapy. Cox multivariate analysis identified SSTR2 and EGFR as independent poor predictors of PFS. CONCLUSION: Our study is the first to shed light on the intricate relationship between SSTR2 and EGFR in NPC and provides new insights into the potential benefits of EGFR targeted therapy for patients with high SSTR2 expression. Additionally, SSTR2 has potential as a new biomarker for poor prognosis in NPC patients.

Role of ß-catenin in PD-L1 expression of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a particular type of tumor connected to Epstein-Barr virus infection, genetic, and environmental factors. It is typically discovered late, with few therapeutic options and poor clinical outcomes. Cellular immune responses can be attenuated when programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) are combined. Although PD-1 inhibitors have a different anti-tumor response rate than chemotherapy alone, they can nevertheless considerably outperform chemotherapy in patients with metastatic or recurrent NPC. The nuclear ß-catenin can bind to the CD274 promoter region, promoting transcription and upregulating the expression of tumor-specific PD-L1. Separation of ß-catenin from E-cadherin and translocation it into nucleus were both aided by ß-catenin phosphorylates at the Tyr654 site. Its function in NPC and the expression of PD-L1 have not yet been investigated. This study investigated the predictive significance of PD-L1 and p-ß-cateninTyr654 expressions in NPC. Our findings indicated that patients with distant metastases or poor prognoses exhibited higher levels of PD-L1 and p-ß-cateninTyr654 expressions. According to Cox multivariate prognostic analysis, PD-L1 was also an effective indicator for predicting the survival status of patients with NPC. We subsequently demonstrated that PD-L1 transcription and protein production could be downregulated by targeting inhibition of the level of ß-catenin in NPC cells. This is for developing the ß-catenin or TCF4 inhibitor as a potential new option for immune checkpoint immunosuppression in NPC.

[Corrigendum] CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation.

Subsequently to the publication of the above article, the authors contacted the Editorial Office to explain that they had inadvertently included data from the same original source in the first row of data panels in Fig. 4B on p. 2191 (showing the results of cell migration assay experiments) to represent two differently performed experiments. Specifically, these images (second and third data panels) containing partially overlapping data corresponded to the 'Vacant­BGC823' in the empty plasmid transfection group and the background 'BGC823 cell' groups, respectively. However, the authors had retained their original data, which they presented to the office for our inspection, and were able to reassemble the data correctly in the figure. The revised version of Fig. 4, showing the replacement data for the 'Vacant­BGC823' and 'BGC823' Migration panels in Fig. 4B, is shown on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 48: 2184­2196, 2016; DOI: 10.3892/ijo.2016.3428].

YAP1 synergize with YY1 transcriptional co-repress DUSP1 to induce osimertinib resistant by activating the EGFR/MAPK pathway and abrogating autophagy in non-small cell lung cancer.

YAP1 is a well-known core effector of the Hippo pathway in tumors, but its potential role in osimertinib resistance remained unexplored. Our study provides evidence that YAP1 acts as a potent promoter of osimertinib resistance. By inhibiting YAP1 with a novel inhibitor, CA3, and combining it with osimertinib, we observed a significant suppression of cell proliferation and metastasis, induction of apoptosis and autophagy, and a delay in the emergence of osimertinib resistance. Interestingly, CA3 combined with osimertinib executed its anti-metastasis and pro-tumor apoptosis in part through autophagy. Mechanistically, we found that YAP1, in collaboration with YY1, transcriptionally represses DUSP1, leading to the dephosphorylation of the EGFR/MEK/ERK pathway and YAP1 phosphorylation in osimertinib-resistant cells. Our results also validate that CA3, in combination with osimertinib, executes its anti-metastasis and pro-tumor apoptosis partly through autophagy and the YAP1/DUSP1/EGFR/MEK/ERK regulatory feedback loop in osimertinib-resistant cells. Remarkably, our findings illustrate that YAP1 protein is upregulated in patients after osimertinib treatment and osimertinib resistance. Overall, our study confirms that the YAP1 inhibitor CA3 increases DUSP1 with concomitant activation of the EGFR/MAPK pathway and induces autophagy to enhance the efficacy of third-generation EGFR-TKI treatments for NSCLC patients.

Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity.

Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promising Cycloguanil analogues from NCI databases, which were cross-referenced with NCI-60 Human Tumor Cell Line Screening data. Using target engagement assays, it was found that these compounds engage DHFR in cells at sub-nanomolar concentrations; however, growth impairments were not observed until higher concentrations. Folinic acid treatment rescues the viability impairments induced by some, but not all, Cycloguanil analogues, suggesting these compounds may have additional targets. Cycloguanil and its most promising analogue, NSC127159, induced similar metabolite profiles compared to established DHFR inhibitors Methotrexate and Pyrimethamine while also blocking downstream signaling, including STAT3 transcriptional activity. These data confirm that Cycloguanil and its analogues are potent inhibitors of human DHFR, and their anti-cancer activity may be worth further investigation.

Targeting ALDH1A1 to induce Necroptosis in Nasopharyngeal Carcinoma.

ALDH1A1 is one of the highly conserved isoenzymes of the aldehyde dehydrogenase family. It is mainly involved in the metabolism of intracellular aldehydes and forms transcriptional regulators, which are essential for growth and differentiation of normal cells. Overexpression of ALDH1A1 in many malignancies and cancer stem cells (CSCs) is closely associated with poor prognosis and promotes tumor aggressiveness and drug resistance during conventional cancer chemotherapy. In this study, we found that ALDH1A1 had tumor suppressor effects in BRCA, CESC, LIHC, Lung cancer, renal cell carcinoma and PAAD, but tumor-promoting effects in SKCM, GBM, THCA and BLCA. As for the nasopharyngeal carcinoma, ALDH1A1 mainly played a carcinogenic role. We found that although the expression of ALDH1A1 in NPC tissue was lower than that in normal nasopharyngeal mucosal tissue, it was upregulated in patients with higher clinical stages, and correlated with poor patient outcomes. Therefore, we further analyzed the main possible role of ALDH1A1 in NPC by taking GSE12452 dataset. The GSEA enrichment analysis showed that it could inhibit the necroptosis of nasopharyngeal carcinoma cells. Therefore, we used the targeted inhibitor NCT-501 and found that it could inhibit the proliferation and stem cell spheroidization of NPC cells, and induce necroptosis. This study explored the possible role of ALDH1A1 in various tumors and focused on its potential role as a target in NPC. Meanwhile, ALDH1A1 inhibitor preferentially has potential therapeutic value in NPC.

Renal Amyloidosis Secondary to ANCA-Associated Vasculitis: A Case Report.

Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.

Emerging roles of lncRNA in Nasopharyngeal Carcinoma and therapeutic opportunities.

Nasopharyngeal carcinoma (NPC) is a kind of malignant tumor with ethnic and geographical distribution characteristics. However, the molecular mechanisms of NPC are still unclear. Long non encoding RNAs (lncRNAs) are becoming important regulators in gene expression networks, including post transcriptional and post translational regulation of protein, protein complex organization, signal transduction and recombination among cells, which are involved in cancer recognition. Recent evidence shows that lncRNAs play important roles in the occurrence and development of NPC. Therefore, in-depth understanding of abnormal lncRNAs will provide new understanding of the pathogenesis in NPC, and provide new tools for the early diagnosis and treatment of NPC. This article reviews the abnormal lncRNAs in NPC cells and the roles of lncRNAs in the tumorigenesis of NPC. In addition, we also discuss the diagnostic and therapeutic potential of lncRNAs in NPC.

YB1 associates with oncogenetic roles and poor prognosis in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is the malignant tumor arising from the nasopharynx epithelium with ethnic and geographical distribution preference. Y-box binding protein-1 (YB1) is the highly expressed DNA/RNA-binding protein with cold shock domain, and enhanced YB1 expression was proved to be associated with many kinds of malignant tumors. There is no systematic study about the regulation of YB1 and cell proliferation, migration, invasion and stress granules (SGs) in NPC, and the relationship between YB1 expression and clinical characteristics and prognosis of NPC patients. We analyzed the mRNA expression of YBX1 in head and neck squamous carcinoma (HNSC) and NPC in databases, investigated the functions of YB1 in cell proliferation, migration and invasion and SGs formation of NPC cells, and detected expression of YB1 protein in a large scale of NPC samples and analyzed their association with clinicopathological features and prognostic significance of NPC patients. YBX1 mRNA was significantly high expression in HNSC and NPC by bioinformatic analysis, and higher expression of YBX1 mRNA indicated poorer prognosis of HNSC patients. Clinically, the expression of YB1 in NPC tissues was significantly higher than these in the control nasopharyngeal epithelial tissues. We further found that the expression of YB1 had an evidently positive relation with advanced clinical stages of patients with NPC. The overall survival rates (OS) were significantly lower for NPC patients with positive expression of YB1. Multivariate analysis confirmed that positive expression of YB1 was the independent poorer prognostic factor for patients with NPC. Moreover, compared with the immortalized nasopharyngeal epithelial cell line (NP69), the basal level of YB1 in NPC cell lines was significantly higher. Knocking down YB1 may inhibit Akt/mTOR pathway in NPC cells. Knocking down YB1 by small interfering RNAs can reduce the ability of proliferation, migration, invasion and SGs formation of NPC cells. The expression of YB1 in NPC cell lines or patients with NPC was significantly higher. The high expression of YB1 protein may act as one valuable independent biomarker to predict poor prognosis for patients with NPC. Knocking down YB1 may release the malignant phenotype of NPC cells.

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer.

Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.

Renal Amyloidosis Secondary to ANCA-Associated Vasculitis: A Case Report / 中国医学科学杂志(英文版)

Renal amyloidosis secondary to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is extremely rare. Here, we reported a 77-year-old woman with ANCA-associated vasculitis. Renal biopsy with Masson trichrome staining showed pauci-immune crescentic glomerulonephritis, and electron microscopy showed amyloid deposition in the mesangial area. Immunofluorescence revealed kappa light chain and lambda light chain negative. Bone marrow biopsy revealed no clonal plasma cell. Finally, she was diagnosed as ANCA-associated vasculitis with secondary renal amyloid A amyloidosis.

Expression of cancer cell-intrinsic PD-1 associates with PD-L1 and p-S6 and predicts a good prognosis in nasopharyngeal carcinoma.

Aims: Programmed cell death ligand 1 (PD-L1) is the ligand of programmed death 1 (PD-1), which is a host immunity inhibitory receptor. Expression of PD-L1 in diverse tumor types has been widely discussed, while there is little research about tumor intrinsic-PD-1. Phospho-S6 (p-S6) is an important downstream effector in the PI3K/AKT/mTOR pathway. Our study was focused on investigating expression of cancer cell-intrinsic PD-1, PD-L1 and p-S6 proteins and aimed to illustrate their relationship and clinical significances in nasopharyngeal carcinoma (NPC). Methods: The expression of PD-1, PD-L1 and p-S6 proteins in tissues of NPC, non-cancerous nasopharyngeal epithelia, primary cancer and matching metastatic lesion was detected by immunohistochemistry. Results: Expression of PD-1, PD-L1 and p-S6 proteins and co-expression of PD-1 and PD-L1 were significantly higher in NPC (all P<0.05). The expression of PD-1 and co-expression of PD-1 and PD-L1 in paired metastatic NPC were significantly increased (all P<0.01). NPC patients with positive expression of PD-L1 showed significantly higher overall survival rate (P =0.035). However, NPC patients with positive expression PD-1 and p-S6 showed significantly lower overall survival rate (P =0.031, P=0.044, respectively). Interestingly, NPC patients with co-expression of PD-1 and PD-L1 had lower overall survival rate (P=0.042). Multivariate Cox proportional hazard regression analysis confirmed that positive expression of PD-L1 and p-S6 were independent prognostic factors for NPC patients. Conclusions: Expression of cancer cell-intrinsic PD-1 associates with PD-L1 and p-S6 proteins, PD-L1 might serve as a good prognostic biomarker, while p-S6 could be an independent poor prognostic biomarker for NPC patients.

High risk of tubular damage in normoalbuminuric adults with type 2 diabetes for over 14 years.

Highlights The level of urinary α1 -microglobulin to creatinine ratio (A1MCR) increases with longer diabetes duration. Patients with a diabetes duration >14 years have a higher tubular damage rate. Being male and a diabetes duration >14 years have an interaction effect on increased A1MCR.

Dose-dependent effect of human milk on Bronchopulmonary dysplasia in very low birth weight infants.

BACKGROUND AND AIM: Human milk has potential protective effects against bronchopulmonary dysplasia (BPD). However, studies on the association between the dose of human milk and BPD in China are limited. This study aimed to evaluate the dose-dependent effects of human milk on BPD and other neonatal morbidities in very low birth weight (VLBW) infants. METHODS: This retrospective cohort study of preterm infants was conducted on preterm infants of gestational age ≤ 34 weeks and birth weight < 1500 g admitted to the multicenter clinical research database for breastfeeding quality improvement in Jiangsu province. The multivariate analysis was performed to compare the effect outcomes of daily graded doses [1-24 mL/(kg · day), 25-49 mL/(kg · day), and ≥ 50 mL/(kg · day) of body weight] of human milk on neonatal outcomes throughout the first 4 weeks of life versus a reference group receiving no human milk. The models were adjusted for potential confounding variables. RESULTS: Of 964 included infants, 279 (28.9%) received exclusive preterm formula, 128 (13.3%) received 1-24 ml/(kg · day), 139 (14.4%) received 25-49 ml/(kg · day), and 418 (43.4%) received ≥50 ml/(kg · day) human milk for the first 4 weeks of life. Compared with infants receiving exclusive formula, those receiving the highest volume of human milk daily [≥50 mL/(kg · day)] had lower incidences of BPD [27.5% in ≥50 mL/(kg · day) vs 40.1% in 0 mL/(kg · day) human milk, P = 0.001)], moderate and severe BPD [8.9% in ≥50 mL/(kg · day) vs 16.1% in 0 mL/(kg · day), P = 0.004], necrotizing enterocolitis [NEC; 3.8% in ≥50 mL/(kg · day) vs 10.8% in 0 mL/(kg · day), P = 0.001], late-onset sepsis [LOS; 9.3% in ≥50 mL/(kg · day) vs 19.7% in 0 mL/(kg · day), P <0.01], and extrauterine growth retardation [EUGR; 38.5% in ≥50 mL/(kg · day) vs 57.6% in 0 mL/(kg · day), P <0.01)]. The logistic regression indicated that those receiving ≥50 ml/kg · day human milk had lower odds of BPD [adjusted odds ratio (AOR) 0.453; 95% confidence interval (CI): 0.309, 0.666], moderate and severe BPD (AOR 0.430; 95% CI: 0.249, 0.742), NEC (AOR 0.314; 95% CI: 0.162, 0. 607), LOS (AOR 0.420; 95% CI: 0.263, 0.673), and EUGR (AOR 0.685; 95% CI: 0.479, 0.979). CONCLUSIONS: A daily threshold amount of ≥50 ml/(kg · day) human milk in the first 4 weeks of life was associated with lower incidence of BPD as well as NEC, LOS, and EUGR in VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03453502 . Registration date: March 5, 2018. This study was retrospectively registered.

miR-4634 augments the anti-tumor effects of RAD001 and associates well with clinical prognosis of non-small cell lung cancer.

MicroRNA (miRNA) is involved in the physiological and pathological processes of various malignancies. In this study, miRNA microarray analysis showed that miR-4634 levels in A549 cells increased significantly after everolimus (RAD001) treatment. Decreased expression of miR-4634 was also found in non-small-cell lung carcinoma (NSCLC) cell lines and patients' tumors by qPCR. Additionally, a combination of miR-4634 and RAD001 exerted synergistic antitumor efficacy by inhibiting cell proliferation, migration, and colony formation. High expression of miR-4634 was significantly more common in non-cancerous lung tissue than adenocarcinoma or squamous cell carcinoma tissue (72.8%, 45.7%, and 50.9%, respectively; P < 0.001). Furthermore, high expression of miR-4634 was found to be more frequent in patients without lymph node metastasis (P = 0.037) by in-situ hybridization. Importantly, through univariate and multivariate analysis, high miR-4634 expression was associated with better prognosis of NSCLC patients. In conclusion, miR-4634 may act as a tumor suppressor in NSCLC, and to augment the efficacy of RAD001, co-treatment of miR-4634 and RAD001 might be a potential mTOR-targeted cancer therapy strategy for NSCLC patients. High expression of miR-4634 could be an independent good prognostic biomarker for NSCLC.