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Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. In vitro and in vivo effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (SOST) and inhibited SOST mRNA and protein expression. SOST overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, SOST knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/SOST axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The chromosomal locations of lncRNAs (long non-coding RNAs, lncRNAs) infer their biological functions in cancer. Lnc-RAB1A-2, a Ras-related protein Rab-1A (RAB1A) upstream lncRNA, was chosen for assessment of its impact on lung cancer prognosis in a case-based analysis and investigation of its biological function though a series of functional assays. Lnc-RAB1A-2 was significantly upregulated in 276 lung cancer tissues compared with corresponding non-tumor tissues, and its expression level was significantly correlated with clinical stage and metastasis status in lung cancer patients. Patients with high expression levels of this lncRNA had a shorter median survival time (16.0 months vs. 23.0 months, P = 0.011 in southern samples; 8.0 months vs. 19.0 months, P = 0.020 in eastern samples; 13.0 months vs. 19.0 months, P = 0.002 in merged samples) and a higher risk of death than those with lower levels (HR = 1.52; 95% CI = 1.01-2.26, in merged samples). Additionally, overexpression of lnc-RAB1A-2 significantly promoted lung cancer cell proliferation in vitro and in vivo. Further analyses using digital gene expression tag profiling revealed that lnc-RAB1A-2 could affect the expression of fibroblast growth factor 1 (FGF1), a gene involved in the PI3K/AKT/mTOR pathway that is largely activated by RAB1A. FGF1 was confirmed to be a down-stream gene of lnc-RAB1A-2. Collectively, our study demonstrated that lnc-RAB1A-2 is associated with poor lung cancer prognosis by promoting lung cancer development., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70-4.01). These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32-1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.

The Mongolian gerbil (Meriones unguiculatus) has been indicated to be a useful experimental model host for studying nematode. To understand the possibility of the Mongolian gerbil as an animal model of Angiostrongylus cantonensis infection, we investigated the development, migration, and tissue distribution of A. cantonensis and pathological changes in the brain and lungs of the infected Mongolian gerbils. The first stage larvae of A. cantonensis in the stool of the infected gerbils were examined by direct smear method at 45th day postinfection (PI). In addition, a group of the infected gerbils were orally fed with albendazole (100 mg/kg/day/gerbil) at the 8th day PI and continued for 3 consecutive days. The results showed that mortality rate of Mongolian gerbils infected with 10 third stage larvae of A. cantonensis was about 62% at the 30th day PI; the peak period of death was from the 23rd to 30th day PI. About 93% (27/29) of the worms in survivors of infected gerbils could develop to complete sexual maturity at the 46th day PI, and the examinations of 12 gerbils in G3 group revealed that first stage larvae of A. cantonensis could be found in the feces of 4 gerbils at the 45th day PI. About 80% of the worms were in the brain of infected gerbils and 20% in the lungs from the 23rd to 25th day PI; during migration of the worms from the brain to lungs, more than 90% of the worms arrived to the lungs and less than 10% of them still stayed in the brain during from the 45th to 46th day PI. Pathological examination revealed that injuries induced by A. cantonensis in infected gerbils were characterized by eosinophilic meningitis and granulomatous pneumonia. Otherwise, albendazole exhibited a good larvicidal activity in the infected Mongolian gerbils. In contrast with infected control group, no gerbils died in administering albendazole, no worms were recovered, and no nervous system symptoms caused by the infection occurred at the 26th day PI. These findings clearly indicated that Mongolian gerbils should be a potential incomplete permissive host for A. cantonensis and are very susceptive to A. cantonensis infection. Moreover, it has been certified that gerbils as an experimental animal can be used in screening of drug against A. cantonensis. The study provides us a new, selectable experimental animal model for research of A. cantonensis.

The study was to understand the Angiostrongylus cantonensis infectious situation of rodent definitive host, snail intermediate host, and local residents in the west-central region of Guangdong Province in China. The snails Achatina fulica and Pomacea canaliculata collected from the survey place were digested with artificial gastric juice, and the third-stage larvae of A. cantonensis in the snails were examined under microscope. The heart and lung of rats captured from the survey place were taken to check the adult of A. cantonensis. The questionnaire surveys related to the infection of A. cantonensis were taken in local residents randomly selected, and the IgG antibody against A. cantonensis was tested in those residents with enzyme-linked immunosorbent assay (ELISA). A total of 1,391 rats including eight kinds of rats, such as Rattus norvegicus, Rattus flavipectus, Bandicota indica, Rattus sladeni, Mus musculus, Rattus rattoides, Suncus Murinus, and Rattus confucianus, were examined and 132 of them were infected by A. cantonensis, with an average infection rate of 9.49% and a mean intensity of A. cantonensis in infected rats was 9.39. A total of 3,184 snails A. fulica and 3,723 snails P. canaliculata were detected. The average infection rates of them were 25.03% (797/3,184) and 6.50% (242/3,723), respectively. There were 180 positive samples of IgG antibody against A. cantonensis in 1,800 serum samples of the residents, with a positive rate of 10.00%. The west-central region of Guangdong Province is the natural focus of A. cantonensis. In comparison with the investigation results in other regions of China, the infection rate of rat definitive host is at the middle level; in the intermediate host, the infection rate of snail A. fulica is above the middle level, and the infection rate of snail Pomacea canaliculata is below the middle level. Some local residents had already been infected by A. cantonensis or at the risk of being infected.