The facultative anaerobic, invasive Salmonella enterica serovar typhimurium (S. typhimurium) has been shown to retard the growth of established tumors. We wondered if a more effective antitumor response could be achieved in vivo if these bacteria were used as tools for delivering specific molecular antitumor therapeutics. Constitutively activated transcription factor signal transducer and activator of transcription 3 (STAT3) promotes the survival of a number of human tumors. In this study, we investigated the relative efficacies of attenuated S. typhimurium alone or combined with Stat3-specific small interfering RNA (siRNA) in terms of tumor growth and metastasis. The bacteria preferentially homed into tumors over normal liver and spleen tissues in vivo. S. typhimurium expressing plasmid-based Stat3-specific siRNAs significantly inhibited tumor growth, reduced the number of metastastic organs, and extended the life time for C57BL6 mice bearing an implanted prostate tumor, versus bacterial treatment alone. These results suggest that attenuated S. typhimurium combined with an RNA interference approach might be more effective for the treatment of primary as well as metastatic cancer. [Cancer Res 2007;67(12):5859-64]

Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DDP chemosensitivity by stimulating apoptosis and pyroptosis. Moreover, XIST's oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-β effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively. Using DDP-resistant NSCLC cells, mouse xenograft studies verified the oncogenic function of XIST and its ability to inhibit programmed cell death, thereby mediating DDP chemoresistance. These findings suggest that XIST expression may serve as a novel biomarker to predict DDP treatment efficacy, and may help in the design of new therapies to circumvent DDP chemoresistance in NSCLC and other tumor types.

Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass (PBM). Insulin-like growth factor type 1 (IGF-1) levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells (MSCs) from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition. Keywords: osteoblasts; knockout mice; cell migration; IGF receptor; nestin Bone Research (2013) 2: 186-194. doi: 10.4248 /BR201302007 IntroductionBone mass normally peaks in mid to late adolescence, plateaus for several years and then declines over time (1-5). Acquisition of a higher peak bone mass (PBM) in adolescence is associated with reduced subsequent fracture risk, whereas impaired acquisition of PBM or loss of bone in childhood is associated with greater fracture risk. Chronic illness in childhood impairs PBM acquisition. Survival of many chronic illnesses in childhood are leading to a growing incidence of secondary osteoporosis (6). The prevention of secondary osteoporosis in children with chronic illnesses depends on protecting the bones of this at-risk population. However, before treatment can be developed, the regulation of cellular signaling mechanisms involved in the acquisition of bone mass needs to be further elucidated.Janet L. Crane et al. www.boneresearch.org | Bone Research 187The only cells that form new bone are osteoblasts, which are non-replicative mononuclear cells derived from mesenchymal stem cells (MSC) (7-...

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Purpose: Low back pain is a global health problem in which more than 40% is caused by lumbar intervertebral disc degeneration (LDD). ADAMTS-5 (A disintegrin and metalloproteinase with thrombospondin motifs-5) was shown to be involved in LDD by functional analyses. To identify whether there is an association between ADAMTS-5 and LDD, and what is the contribution of ADAMTS-5 genetic polymorphisms to MD (Mean diffusivity) changes in lumbar IVD (Intervertebral disc). We firstly genotyped selected ADAMTS-5 SNPs (Single nucleotide polymorphisms) in a Chinese Han population. After the primary analyses of allelic, genotypic, and haplotypic association, we performed SNP-SNP interaction analysis. We subsequently genotyped another 50 participants and acquired the corresponding MD values from individual lumbar IVDs. The association analysis between the genotypic groups divided by the above positive SNPs and the corresponding MD values were also performed. Significant associations were identified in rs151058, rs229052, and rs162502. None of the 2-SNP haplotypic analysis survived the 10,000 permutation test. The following interaction analysis demonstrated that rs151058 was strong associated with LDD when conditioning on rs162502. Significant difference of MD values between AA and Gþ carriers was identified in rs162502. This is the first study indicating that the SNPs of ADAMTS-5 may contribute to predisposition of LDD. An interaction between rs151058 and rs229052 may exist in ADAMTS-5 with LDD. Keywords: lumbar disc degeneration (LDD); a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5); single nucleotide polymorphism (SNP); diffusion tensor imaging (DTI) As a global health problem, low back pain (LBP) was reported to affect about 80% of population during a lifetime.1 LBP, defined as pain radiating from the back into the dermatome of the affected nerve trunk, is a common musculoskeletal disorder characterized by symptomatic lumbar disc herniation with or without sciatica.2 More than 40% of LBP is caused by lumbar intervertebral disc degeneration (LDD). 3It was reported that about 5% of the Finnish population suffered from LDD, leading to disability in the workingage population. 4 Though several environmental and anthropometric risk factors have been showed to be related to LDD, the roles of genetic factors can never be exaggerated. 5-10The extracellular matrix (ECM), composed of collagens and proteoglycans, is crucial to normal intervertebral disc (IVD) functions.11 Previous studies indicated that the synthesis and degradation balance of ECM was interrupted by diverse matrix proteases during LDD. [12][13][14][15][16] As a large family of metalloproteases, ADAMTS-5 seems to be the most active one, 15,17,18 and has been paid increasing attentions due to their abilities in the cartilage proteoglycan cleavage. 19,20 Besides mRNA and protein of ADAMTS-5 were detected in IVDs, 21 increased levels in patients with chronic LBP and intervertebral disc herniation during LDD can be found. [22][23][24...

Background: To investigate the diagnosis and surgical therapy of delayed diaphragmatic rupture.Methods: Forty patients with traumatic diaphragmatic rupture with delayed presentation and diagnosis were collected in Peking Union Medical College Hospital from 2000 to 2018, and a retrospective analysis was performed. Results: In all forty patients, 36 (90%) patients had a traumatic past history, and 32 (80%) patients had clinical manifestations when diagnosed. Left-sided diaphragmatic rupture was found in 32 (80%) patients and right in 8 (20%) patients. One patient received emergency surgery, and 39 received selective surgery.Thirty-eight patients received thoracotomy, and 2 patients received combined thoracic-abdominal surgery.Thirty-six patients received direct diaphragm suture, and 4 patients received mesh repair. One patient had an intestinal obstruction and received enterolysis 19 days after surgery. During follow-up, 1 patient experienced recurrence 2 years later. Conclusions: Careful recording of past history and physical examination are the best approaches in diagnosing delayed presentation of traumatic diaphragmatic rupture. CT scan with reconstruction of the diaphragm is helpful in both diagnosis and differential diagnosis. Surgical therapy after diagnosis is the best treatment.

Gekko japonicus undergoes dramatic changes in the caudal spinal cord after tail amputation. The amputation induces cell proliferation in the caudal ependymal tube. We performed hematoxylin and eosin staining at different time points in the regeneration process to investigate the morphological characterization of the regenerated appendages. The central canal extended to the blastema post-amputation and the cartilage and muscle tissue appeared 3 weeks after injury. We performed the bromodeoxyuridine (BrdU) incorporation assay to detect proliferating cells during the regeneration process. BrdU positive cells were detected in the peri-central canal. Furthermore, nestin and neuron-specific enolase (NSE) immunocytochemistry were applied to detect neural stem/progenitor cells and neurons. Two weeks after injury, nestin-positive cells undergoing proliferation were located outside of the ependymal tube, and NSE positive cells appeared after 3 weeks of amputation. These data suggest that neurogenesis is an early event during caudal spinal cord regeneration in gecko.

PurposeTo compare the variation patterns of ADC and T2 values in different age and intervertebral disc (IVD) levels, thus to identify their sensitivities in assessing age and disc level related IVDs changes.Materials and MethodsThe T2 and ADC values were recorded from 345 IVDs of 69 volunteers. Kendall's correlation analysis was used to identify the relationship between age and T2/ADC mean values respectively. The one-way analysis of variance (ANOVA) with post hoc analysis was then applied to test the differences of T2 and ADC values among different IVD levels and age groups, followed by linear regression analysis between age (<45 and >45 years) and T2/ADC mean values. This study was approved by the Ethics Committee of the Chinese Academy of Medical Sciences and the Peking Union Medical College Hospital.ResultsSignificant negative correlation was observed between age and T2/ADC mean values. The T2 and ADC values showed significant differences among IVD levels and among age groups except for T2 values in age group 1 (25–34 years) and group 2 (35–44 years), and for ADC values at L1–2 level. Both T2 and ADC values showed significant differences between young (age<45 years) and elderly group (age>45 years) at each IVD level. A linear relationship was observed between age and T2/ADC mean values in the elderly group as well as in the young group for the ADC mean values, while no such tendency was identified in the young group for the T2 mean values.ConclusionsADC values may be a more sensitive parameter than T2 in assessing age and disc level related intervertebral disc changes.