Metal-dependent programmed cell death-related lncRNA prognostic signatures and natural drug sensitivity prediction for gastric cancer.

Background: Gastric cancer is one of the most important malignancies with poor prognosis. Ferroptosis and cuproptosis are newly discovered metal-dependent types of programmed cell death, which may directly affect the outcome of gastric cancer. Long noncoding RNAs (lncRNAs) can affect the prognosis of cancer with stable structures, which could be potential prognostic prediction factors for gastric cancer. Methods: Differentially expressed metal-dependent programmed cell death (PCD)-related lncRNAs were identified with DESeq2 and Pearson's correlation analysis. Through GO and KEGG analyses and GSEA , we identified the potential effects of metal-dependent PCD-related lncRNAs on prognosis. Using Cox regression analysis with the LASSO method, we constructed a 12-lncRNA prognostic signature model. Also, we evaluated the prognostic efficiency with Kaplan-Meier (K-M) survival curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) methods. The sensitivities for antitumor drugs were then predicted with the pRRophetic method. Also, we discuss Chinese patent medicines and plant extracts that could induce metal-dependent programmed cell death. Results: We constructed a metal-dependent PCD-related lncRNA-gene co-expression network. Also, a metal-dependent PCD-related gastric cancer prognostic signature model including 12 lncRNAs was constructed. The K-M survival curve revealed a poor prognosis in the high-risk group. ROC curve analysis shows that the AUC of our model is 0.766, which is better than that of other published models. Moreover, the half-maximum inhibitory concentration (IC50) for dasatinib, lapatinib, sunitinib, cytarabine, saracatinib, and vinorelbine was much lower among the high-risk group. Conclusion: Our 12 metal-dependent PCD-related lncRNA prognostic signature model may improve the OS prediction for gastric cancer. The antitumor drug sensitivity analysis results may also be helpful for individualized chemotherapy regimen design.

[Retracted] miR­133a inhibits cervical cancer growth by targeting EGFR.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data in Fig. 5c were strikingly similar to data appearing in different form in other articles by different authors at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 34: 1573­1580, 2015; DOI: 10.3892/or.2015.4101].

Subcutaneous panniculitis-like T-cell lymphoma invading central nervous system in long-term clinical remission with lenalidomide: A case report.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) involvement in the central nervous system (CNS) is particularly rare. SPTCL with CNS involvement has an exceedingly poor prognosis, and no optimum therapeutic method has been discovered. To the best of our knowledge, this is the first reported case of SPTCL invading the CNS achieving long-term remission with lenalidomide maintenance therapy. CASE SUMMARY: A 63-year-old man diagnosed with SPTCL was admitted to the hospital with severe headache for 15 d after four cycles of chemotherapy. Subsequent to the treatment, the patient developed CNS involvement. Craniotomy biopsy was pathologically diagnosed as CNS T-cell lymphoma, and two courses of chemotherapy were performed postoperatively. Due to the intolerance of the side effects of chemotherapeutic drugs, the patient received lenalidomide instead. The magnetic resonance imaging of the head at the 8 mo follow-up indicated no signs of recurrence, and the vital signs were stable. CONCLUSION: Lenalidomide deserves further investigation as a targeted drug for SPTCL cases involving the CNS.

A meta-analysis of naldemedine for the treatment of opioid-induced constipation.

INTRODUCTION: Opioid-induced constipation (OIC) is a common adverse effect in patients under long-term opioid therapy. Naldemedine is a novel peripherally acting µ-opioid receptor antagonists being developed for the treatment of OIC without affecting central analgesia. This meta-analysis is to assess the current evidence for efficacy and safety of naldemedine for the treatment of OIC. Areas covered: We searched through MEDLINE, EMBASE, Web of Science and Cochrane Library, 'ISRCTN Register' and'ClinicalTrials.gov' (up to Aug 2018). Our final review included five randomized clinical trials (1751 participants in total), three trials observed naldemedine for the treatment of OIC in non-cancer patients and two trials in cancer patients. A Random Effects model was used for all comparisons. Subgroup analyses for the following subgroups were carried out: naldemedine 0.1 mg; 0.2 mg; 0.4 mg; cancer patients; non-cancer patients. Expert opinion: Naldemedine improved the proportion of responders and spontaneous bowel movements frequency. The incidence of serious adverse effects (AEs) in naldemedine group was higher than placebo, especially in cancer patient subgroup. The AEs occurred in participants with naldemedine were mild to moderate and well tolerated during treatment. The results of this network meta-analysis will guide the future researchers in evaluating naldemedine for the treatment of OIC.

Leptin and leptin receptor genes in tongue sole (Cynoglossus semilaevis): Molecular cloning, tissue distribution and differential regulation of these genes by sex steroids.

Leptin (Lep) is a key factor for the regulation of food intake and energy homeostasis in mammals. To date, a number of studies have provided evidence for the existence of multiple leptin genes in teleosts, but not much information is available in fish regarding the regulation of leptin genes by sex steriods. As a first step, two leptin genes (lepa and lepb) and a leptin receptor (lepr) gene were cloned from the half-smooth tongue sole (Cynoglossus semilaevis), a representative species of the order Pleuronectiformes. The full-length cDNAs of tongue sole lepa and lepb were 1265 bp and 1157 bp in length, encoding for proteins of 160 aa and 158 aa, respectively. The three-dimensional structures modeling of tongue sole LepA and LepB showed strong conservation of tertiary structure with other vertebrates. The full-length cDNA of tongue sole lepr was 4576 bp, encoding a protein of 1133 aa which contained all functionally important domains conserved among vertebrate LepRs. Tissue distribution analysis showed that tongue sole lepa mRNA was highly detectable in the ovary and brain, while lepb mRNA was ubiquitously expressed in various tissues. Notably, the tongue sole lepr mRNA was most abundant in the ovary. Using a primary hepatocyte culture system, we evaluated the effects of sex steroids on lep/lepr gene expression. Both 17ß-estradiol (E2) and testosterone (T) inhibited hepatic lepa and lepr mRNAs without affecting lepb mRNA levels. In addition, T also suppressed growth hormone receptor 1 (ghr1), ghr2, and insulin-like growth factor 2 (igf-2) mRNA levels, and stimulated expression of igf-1 gene. On the other hand, none of these four genes were altered by E2. To the best of our knowledge, this is the first description of a direct and differential regulation of lep/lepr gene expression by sex steroids at the hepatocyte level of a flatfish, supporting that individual leptin peptide may possess different biological roles in teleosts.

Molecular characterization of kiss2 and differential regulation of reproduction-related genes by sex steroids in the hypothalamus of half-smooth tongue sole (Cynoglossus semilaevis).

Kisspeptin (Kiss) plays a critical role in mediating gonadal steroid feedback to the gonadotropin-releasing hormone (GnRH) neurons in mammals. However, little information regarding the regulation of kisspeptin gene by sex steroids is available in teleosts. In this study, we examined the direct actions of estradiol (E2) and testosterone (T) on hypothalamic expression of kisspeptin and other key factors involved in reproductive function of half-smooth tongue sole. As a first step, a partial-length cDNA of kiss2 was identified from the brain of tongue sole and kiss2 transcript levels were shown to be widely expressed in various tissues, notably in the ovary. Then, the actions of sex steroids on kiss2 and other reproduction-related genes were evaluated using a primary hypothalamus culture system. Our results showed that neither kiss2 nor its receptor kiss2r mRNA levels were significantly altered by sex steroids. Moreover, sex steroids did not modify hypothalamic expression of gonadotropin-inhibitory hormone (gnih) and its receptor gnihr mRNAs, either. However, E2 markedly stimulated both gnrh2 and gnrh3 mRNAs levels. Overall, this study provides insights into the role of sex steroids in the reproductive function of Pleuronectiform teleosts.

Chitosan Oligosaccharide Reduces Propofol Requirements and Propofol-Related Side Effects.

Propofol is one of the main sedatives but its negative side effects limit its clinical application. Chitosan oligosaccharide (COS), a kind of natural product with anti-pain and anti-inflammatory activities, may be a potential adjuvant to propofol use. A total of 94 patients receiving surgeries were evenly and randomly assigned to two groups: 10 mg/kg COS oral administration and/or placebo oral administration before being injected with propofol. The target-controlled infusion of propofol was adjusted to maintain the values of the bispectral index at 50. All patients' pain was evaluated on a four-point scale and side effects were investigated. To explore the molecular mechanism for the functions of COS in propofol use, a mouse pain model was established. The activities of Nav1.7 were analyzed in dorsal root ganglia (DRG) cells. The results showed that the patients receiving COS pretreatment were likely to require less propofol than the patients pretreated with placebo for maintaining an anesthetic situation (p < 0.05). The degrees of injection pain were lower in a COS-pretreated group than in a propofol-pretreated group. The side effects were also more reduced in a COS-treated group than in a placebo-pretreated group. COS reduced the activity of Nav1.7 and its inhibitory function was lost when Nav1.7 was silenced (p > 0.05). COS improved propofol performance by affecting Nav1.7 activity. Thus, COS is a potential adjuvant to propofol use in surgical anesthesia.

Attenuation Effect of Spinal Manipulation on Neuropathic and Postoperative Pain Through Activating Endogenous Anti-Inflammatory Cytokine Interleukin 10 in Rat Spinal Cord.

OBJECTIVES: The purpose of this study was to investigate roles of the anti-inflammatory cytokine interleukin (IL) 10 and the proinflammatory cytokines IL-1ß and tumor necrosis factor α (TNF-α) in spinal manipulation-induced analgesic effects of neuropathic and postoperative pain. METHODS: Neuropathic and postoperative pain were mimicked by chronic compression of dorsal root ganglion (DRG) (CCD) and decompression (de-CCD) in adult, male, Sprague-Dawley rats. Behavioral pain after CCD and de-CCD was determined by the increased thermal and mechanical hypersensitivity of the affected hindpaw. Hematoxylin and eosin staining, whole-cell patch clamp electrophysiological recordings, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the neural inflammation, neural excitability, and expression of c-Fos and PKC as well as levels of IL-1ß, TNF-α, and IL-10 in blood plasma, DRG, or the spinal cord. We used the activator adjusting instrument, a chiropractic spinal manipulative therapy tool, to deliver force to the spinous processes of L5 and L6. RESULTS: After CCD and de-CCD treatments, the animals exhibited behavioral and neurochemical signs of neuropathic pain manifested as mechanical allodynia and thermal hyperalgesia, DRG inflammation, DRG neuron hyperexcitability, induction of c-Fos, and the increased expression of PKCγ in the spinal cord as well as increased level of IL-1ß and TNF-α in DRG and the spinal cord. Repetitive Activator-assisted spinal manipulative therapy significantly reduced simulated neuropathic and postoperative pain, inhibited or reversed the neurochemical alterations, and increased the anti-inflammatory IL-10 in the spinal cord. CONCLUSION: These findings show that spinal manipulation may activate the endogenous anti-inflammatory cytokine IL-10 in the spinal cord and thus has the potential to alleviate neuropathic and postoperative pain.

Mixed primary squamous cell carcinoma, follicular carcinoma, and micropapillary carcinoma of the thyroid gland: A case report.

Primary squamous cell carcinoma of the thyroid gland is rare, and mixed squamous cell and follicular carcinoma is even rarer still, with only a few cases reported in the literature. The simultaneous presentation of three primary cancers of the thyroid has not been reported previously. Here we report a case of primary squamous cell carcinoma of the thyroid, follicular thyroid carcinoma, and micropapillary thyroid carcinoma. A 62-year-old female patient presented with complaints of pain and a 2-month history of progressively increased swelling in the anterior region of the neck. Fine-needle-aspiration cytology of both lobes indicated the possibility of the presence of a follicular neoplasm. Total thyroidectomy with left-sided modified radical neck dissection was performed. Postoperative pathological examination confirmed the diagnosis of thyroid follicular carcinoma with squamous cell carcinoma and micropapillary carcinoma of the thyroid. Thyroid-stimulating hormone suppressive therapy with l-thyroxine was administered. Radioiodine and radiotherapy also were recommended, but the patient did not complete treatment as scheduled. The patient remained alive more than 9 months after operation. The present case report provides an example of the coexistence of multiple distinct malignancies in the thyroid.

miR-133a inhibits cervical cancer growth by targeting EGFR.

MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in cervical carcinogenesis and progression. microRNA-133a (miR-133a) has been reported to play a tumor-suppressor role in a range of cancers. However, the role and underlying molecular mechanism of miR-133a in cervical cancer have not been investigated. In the present study, we investigated the role of miR-133a in the tumorigenicity of cervical cancer cells in vivo and in vitro. The expression of miR-133a was investigated using real-time reverse transcription-polymerase chain reaction (qRT-PCR) in 30 cervical specimens and matched adjacent normal tissues and cervical cancer cell lines. We found that the expression level of miR­133a was significantly downregulated in cervical cancer tissues and cervical cancer cell lines, and the aberrant expression of miR-133a was correlated with lymph node metastasis, histological grade and FIGO stage. The role of miR-133a in tumorigenicity of cervical cancer cells was assessed by the restoration of miR-133a. We found that restoration of miR­133a inhibited cell proliferation, colony formation, migration and invasion, promoted cell apoptosis in vitro and suppressed tumorigenicity in vivo. The epidermal growth factor receptor (EGFR) was confirmed to be a direct target of miR-133a in cervical cancer cells using luciferase assay and western blotting. Restoration of miR-133a inhibited EGFR expression and activated the AKT and ERK signaling pathways. These results showed that miR-133a suppresses cervical cancer growth in vitro and in vivo through targeting EGFR, suggesting that miR-133a can be a potential target for the treatment of cervical cancer.

EphB receptor signaling in mouse spinal cord contributes to physical dependence on morphine.

Cellular and molecular mechanisms underlying opioid tolerance and dependence remain elusive. We investigated roles of EphB receptor tyrosine kinases--which play important roles in synaptic connection and plasticity during development and in the matured nervous system--in development and maintenance of physical dependence on morphine in the mouse spinal cord (SC). Spinal administration of an EphB receptor blocking reagent EphB2-Fc prevents and/or suppresses behavioral responses to morphine withdrawal and associated induction of c-Fos and depletion of calcitonin gene-related peptide. Western blotting and immunohistochemical fluorescence staining demonstrates that EphB1 receptor protein is significantly up-regulated in the spinal dorsal horn following escalating morphine treatment. Chronic morphine exposure and withdrawal significantly increased phosphorylation of N-methyl-D-aspartate receptor subunit NR2B as well as the activated forms of extracellular signal-regulated kinase and the cAMP response element binding protein in SC. The increased levels of phosphorylation of these molecules, however, are significantly inhibited by the EphB receptor blocker. These findings indicate that EphB receptor signaling, probably by interacting with NR2B in SC, contributes to the development of opioid physical dependence and withdrawal effects. This novel role for EphB receptor signaling suggests that these molecules may be useful therapeutic targets for preventing, minimizing, or reversing the development of opiate dependence.

Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats.

AIM: To investigate whether activation and translocation of extracellular signal-regulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain. METHODS: Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciaticaos trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis. RESULTS: Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord. CONCLUSION: The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.