MicroRNA-16 inhibits the TLR4/NF-κB pathway and maintains tight junction integrity in irritable bowel syndrome with diarrhea.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic and relapsing inflammatory disorder in which pathogenesis has been shown to be in part the result of miRNA-mediated signaling. Here, we investigated the alleviatory role of miR-16 in IBS-D. First, we established an IBS-D mouse model using colonic instillation of acetic acid and developed an IBS-D cell model using lipopolysaccharide exposure. The experimental data demonstrated that miR-16 was underexpressed in the serum of IBS-D patients, as well as in the colorectal tissues of IBS-D mouse models and lipopolysaccharide-exposed intestinal epithelial cells. Next, miR-16 and TLR4 were overexpressed or inhibited to characterize their roles in the viability and apoptosis of intestinal epithelial cells, inflammation, and epithelial tight junction. We found that miR-16 overexpression increased the viability of intestinal epithelial cells, maintained tight junction integrity, and inhibited cell apoptosis and inflammation. We showed that miR-16 targeted TLR4 and inhibited the TLR4/NF-κB signaling pathway. Additionally, inhibition of NF-κB suppressed the long noncoding RNA XIST, thereby promoting enterocyte viability, inhibiting apoptosis and cytokine production, and maintaining tight junction integrity. In vivo experiments further verified the alleviatory effect of miR-16 on IBS-D symptoms in mice. Taken together, we conclude that miR-16 downregulates XIST through the TLR4/NF-κB pathway, thereby relieving IBS-D. This study suggests that miR-16 may represent a potential target for therapeutic intervention against IBS-D.

Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer.

Esophageal cancer (EC) is a main cause of cancer-related deaths. However, genomic alterations and the clinical value of next-generation sequencing (NGS) in advanced or metastatic EC for precision therapy remain largely unclear. Herein, we performed comprehensive analyses on a cohort of 47 individuals with advanced or metastatic EC who underwent NGS between May 2017 and February 2020. Eventually, 227 mutated genes were identified in the cohort. TP53, NQO1, DPYD, GSTM1, XRCC1 and ERCC1 were the most mutated genes and associated with immune cell infiltration, autophagy and hypoxia. Patients who received NGS-guided treatments exhibited better objective remission rate (ORR) (72.22%), disease control rate (DCR) (88.89%), overall survival (OS) (P = .0019) and progression-free survival (PFS) (P = .0077) than those not receiving NGS-guided therapies. The multivariate analyses further demonstrated that the NGS-guided therapy was an independently prognostic factor (OS: hazard radio [HR] 0.31, 95% coincidence interval [CI] 0.1-0.97, P = .04). In conclusion, we depicted a comprehensive mutational landscape of 47 patients with locally advanced or metastatic EC and illustrated the utility of NGS testing to guide clinical management in improving ORR, DCR, OS and PFS.

Circ-LARP1B knockdown restrains the tumorigenicity and enhances radiosensitivity by regulating miR-578/IGF1R axis in hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Circular RNA La Ribonucleoprotein 1B (circ-LARP1B) was reported to serve as an oncogene in many types of cancers. Radiotherapy (RT) is an important element of the multimodal treatment concept in malignancies. Here, this work aimed to investigate the role of circ-LARP1B in the tumorigenesis and radiosensitivity of hepatocellular carcinoma (HCC). PATIENTS OR MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of genes and proteins. In vitro experiments were conducted using cell counting Kit-8 (CCK-8), colony formation, EDU, transwell, and tube formation assays, respectively. Dual-luciferase reporter assay was employed to identify the target relationship between miR-578 and circ-LARP1B or IGF1R (insulin-like growth factor 1 receptor). In vivo assay was performed using murine xenograft model. RESULTS: Circ-LARP1B was highly expressed in HCC tissues and cells, and high expression of circ-LARP1B was closely associated with poor prognosis. Functional experiments demonstrated that circ-LARP1B silencing impaired cell proliferation, invasion, angiogenesis and reduced radioresistance in vitro. Mechanistically, circ-LARP1B could competitively bind with miR-578 to relieve the repression of miR-578 on the expression of its target gene IGF1R. Further rescue assay confirmed that miR-578 inhibition reversed the inhibitory effects of circ-LARP1B knockdown on HCC cell malignant phenotypes and radioresistance. Moreover, miR-578 overexpression restrained tumorigenicity and enhanced radiosensitivity in HCC cells, which were attenuated by IGF1R up-regulation. Besides that, circ-LARP1B knockdown impeded tumor growth and enhanced irradiation sensitivity in HCC in vivo. CONCLUSIONS: Circ-LARP1B knockdown restrained HCC tumorigenicity and enhanced radiosensitivity by regulating miR-578/IGF1R axis, providing a new target for the treatment of HCC.

Prognostic values, ceRNA network, and immune regulation function of SDPR in KRAS-mutant lung cancer.

BACKGROUND: Serum Deprivation Protein Response (SDPR) plays an important role in formation of pulmonary alveoli. However, the functions and values of SDPR in lung cancer remain unknown. We explored prognostic value, expression pattern, and biological function of SDPR in non-small cell lung cancer (NSCLC) and KRAS-mutant lung cancers. METHODS: SDPR expression was evaluated by quantitative real-time PCR (RT-qPCR), immunohistochemistry (IHC), and Western blot on human NSCLC cells, lung adenocarcinoma tissue array, KRAS-mutant transgenic mice, TCGA and GEO datasets. Prognostic values of SDPR were evaluated by Kaplan-Meier and Cox regression analysis. Bioinformatics implications of SDPR including SDPR-combined transcription factors (TFs) and microRNAs were predicted. In addition, correlations between SDPR, immune checkpoint molecules, and tumor infiltration models were illustrated. RESULTS: SDPR expression was downregulated in tumor cells and tissues. Low SDPR expression was an independent factor that correlated with shorter overall survival of patients both in lung cancer and KRAS-mutant subgroups. Meanwhile, ceRNA network was constructed to clarify the regulatory and biological functions of SDPR. Negative correlations were found between SDPR and immune checkpoint molecules (PD-L1, TNFRSF18, TNFRSF9, and TDO2). Moreover, diversity immune infiltration models were observed in NSCLC with different SDPR expression and copy number variation (CNV) patterns. CONCLUSIONS: This study elucidated regulation network of SDPR in KRAS-mutant NSCLC, and it illustrated correlations between low SDPR expression and suppressed immune system, unfolding a prognostic factor and potential target for the treatment of lung cancer, especially for KRAS-mutant NSCLC.

PRINCESS: Privacy-protecting Rare disease International Network Collaboration via Encryption through Software guard extensionS.

Motivation: We introduce PRINCESS, a privacy-preserving international collaboration framework for analyzing rare disease genetic data that are distributed across different continents. PRINCESS leverages Software Guard Extensions (SGX) and hardware for trustworthy computation. Unlike a traditional international collaboration model, where individual-level patient DNA are physically centralized at a single site, PRINCESS performs a secure and distributed computation over encrypted data, fulfilling institutional policies and regulations for protected health information. Results: To demonstrate PRINCESS' performance and feasibility, we conducted a family-based allelic association study for Kawasaki Disease, with data hosted in three different continents. The experimental results show that PRINCESS provides secure and accurate analyses much faster than alternative solutions, such as homomorphic encryption and garbled circuits (over 40 000× faster). Availability and Implementation: https://github.com/achenfengb/PRINCESS_opensource. Contact: shw070@ucsd.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Efficacy and outcome analysis: Combination of Endostar and chemotherapy as a neoadjuvant treatment of stage IIIA/IIIB squamous cell lung cancer.

Patients with stage IIIA/IIIB squamous non-small cell lung cancer (SqCLC) are particularly challenging to treat with a poor 5-year survival rate and new treatment strategies are needed. In the present study, a retrospective, single-center study was conducted to explore the efficacy and safety of Endostar combined with chemotherapy as the neoadjuvant treatment in patients with stage IIIA/IIIB SqCLC. A total of 27 patients with locally advanced SqCLC treated with Endostar combined with chemotherapy as neoadjuvant therapy from January 1, 2017 to December 31, 2019 at the Zhejiang Cancer Hospital (Hangzhou, China) were included. Short-term efficacy, rate of surgical resection, long-term outcome and adverse events were analyzed. After treatment with Endostar combined with chemotherapy, 37% of the patients underwent surgery and the radical resection rate was 90%. The objective response rate was 63% for the total population and 80% for patients who received surgery. Of note, 100% of the patients achieved disease control after treatment with Endostar combined with chemotherapy. In patients who underwent surgical resection, postoperative pathology showed that 100% of the patients achieved pathological downstaging. Furthermore, 1 (10%) patient showed a pathological complete response after surgery. The median progression-free survival was 13.5 months and overall survival was 27.9 months for the total cohort. The most common adverse events (AEs) were anemia (69.4% of patients), followed by hypertension (29.6% of patients). Most of the AEs were grade 1-2 and only 4 patients (14.8%) developed grade 3-4 AEs. Endostar combined with chemotherapy was well-tolerated and showed promising efficacy in patients with stage IIIA/IIIB SqCLC. Further prospective studies are warranted to explore its value as a neoadjuvant therapy.

Screening and evaluation of bamboo shoots: Comparing the content of trace elements from 100 species.

Hundreds of bamboo shoots have been reported to be edible, but the accumulation of trace elements and hazardous elements in bamboo shoots is poorly understood. Here, 100 bamboo species have been evaluated by screening elements including B, Fe, Mn, Cu, Zn, Cd, Pb and As in bamboo shoots using different assessment systems. Bamboo shoots displayed different morphological characteristics, and large differences were found in the concentration of elements. Most bamboo shoots were rich in Fe and Zn and low concentrations of hazardous elements, but the concentration of Cd and Pb exceeded the maximum permissible limits of tuber vegetables in some bamboo species. Different bamboo shoots were ranked differently in the four assessment systems, and the comprehensive evaluation assigned final scores to all 100 bamboo shoots. This study provides valuable recommendations for selecting high-quality bamboo shoots that are rich in trace elements nutrition while minimizing the potential for hazardous element accumulation.

Targeted therapies for RET-fusion cancer: Dilemmas and breakthrough.

Genomic profiling has revolutionized treatment options for patients with oncogene-driven cancers, such as epidermal growth factor receptor (EGFR) mutant carcinoma. Rearranged during transfection (RET) rearrangement, as one of the main activated oncogenes, has been well studied and found to be involved in the malignant behavior of carcinogenesis, resulting in acquired resistance to EGFR tyrosine kinase inhibitors and inducing an intrinsic resistance to immunotherapy. Thus, targeted therapies have been investigated against RET arrangement cancers, including several multi-kinase inhibitors and selective RET inhibitors. However, modest efficacy, a relatively high rate of toxicity, and poor effectiveness against brain metastasis are common limitations of multi-targeted novel molecular inhibitors. A promising prospect was shown recently in selective RET inhibitors in several ongoing clinical trials. In this review, we reviewed the concurrent dilemmas of targeted therapies against RET arrangement cancer from preclinical and clinical studies and proposed several clinical considerations for clinical practice prospectively.

Dual inhibition of VEGF and PARP suppresses KRAS-mutant colorectal cancer.

The addition of bevacizumab to chemotherapy has prolonged overall and progression-free survival rates for metastatic colorectal cancer (mCRC). However, KRAS-mutant (KRAS-mut) CRC, lacking an ideal targeted agent, represents an inferior-response subgroup of patients. In the present study, we investigated a combination approach of bevacizumab + olaparib in KRAS-mut CRC in a preclinical setting. The combined therapy effectively prevented tumor growth in a KRAS-mut cancer cell-derived xenograft model, although this effect was not observed in vitro. Under bevacizumab treatment, we detected intratumor hypoxia and impaired homologous recombination repair (HRR), accompanied by vascular regression. We explored the underlying mechanism of this combined therapy by mimicking a hypoxic condition in vitro using cobalt chloride (CoCl2). The results showed that hypoxia impairs HRR and therefore sensitized KRAS-mut CRC cell lines HCT-116, SW620, and Lovo to olaparib. Furthermore, under this hypoxic condition, olaparib could arrest the cell cycle in the G2/M phase, increase DNA damage and dramatically induce cell apoptosis in KRAS-mut CRC cells. Taken together, these results indicated that the combination of bevacizumab + olaparib could be a potential therapeutic approach in a KRAS-mut CRC cohort.

Impact of molecular subtypes on metastatic behavior and overall survival in patients with metastatic breast cancer: A single-center study combined with a large cohort study based on the Surveillance, Epidemiology and End Results database.

Breast cancer is a highly heterogeneous disease at the molecular level and >90% of mortalities are due to metastasis and its associated complications. The present study determined the impact of molecular subtypes on metastatic behavior and overall survival (OS) of patients with metastatic breast cancer. The influence of molecular subtypes on the sites and number of metastases in 166 patients with metastatic breast cancer from a single center were assessed; and the influence of molecular subtypes on the sites and number of metastases and OS in 15,322 metastatic cases among 329,770 patients with primary breast cancer from the Surveillance, Epidemiology and End Results database were assessed. Analysis of both datasets revealed that different molecular subtypes exhibited differences in the prevalence of different metastatic sites and number of metastases. A larger proportion of bone metastasis was observed in the hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+ subtype than in other subtypes, more lung metastasis was observed in the HR-/HER2+ subtype and more liver metastasis occurred in the HR+/HER2+ and HR-/HER2+ subtypes. Single-site metastasis was more common for the HR+/HER2- subtype than in other subtypes, while 2-3 sites of metastases were more common for the HR+/HER2+ subtype and ≥4 sites of metastases were more frequent in the HR-/HER2+ and HR-/HER2- subtypes. The mean OS of patients with primary breast cancer in the HR+/HER2- subtype group was the longest (78.5 months), while the HR-/HER2- group had the shortest mean OS (69.1 months). The mean OS of the metastatic HR+/HER2+ group was the longest (46.0 months), while the mean OS of the metastatic HR-/HER2- group was the shortest (18.5 months). In conclusion, the results of the present study suggested that different molecular subtypes of breast cancer have different metastatic behavior, as well as mean OS.

PREMIX: PRivacy-preserving EstiMation of Individual admiXture.

In this paper we proposed a framework: PRivacy-preserving EstiMation of Individual admiXture (PREMIX) using Intel software guard extensions (SGX). SGX is a suite of software and hardware architectures to enable efficient and secure computation over confidential data. PREMIX enables multiple sites to securely collaborate on estimating individual admixture within a secure enclave inside Intel SGX. We implemented a feature selection module to identify most discriminative Single Nucleotide Polymorphism (SNP) based on informativeness and an Expectation Maximization (EM)-based Maximum Likelihood estimator to identify the individual admixture. Experimental results based on both simulation and 1000 genome data demonstrated the efficiency and accuracy of the proposed framework. PREMIX ensures a high level of security as all operations on sensitive genomic data are conducted within a secure enclave using SGX.