Systemic Inflammatory Biomarkers Predict Survival of Patients Treated With Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma.

OBJECTIVE: We aimed to retrospectively investigate whether the neutrophil to lymphocyte ratio (NLR) and the monocyte to lymphocyte ratio (MLR) can predict the prognosis of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib or sorafenib. METHODS: We retrospectively identified 210 patients with mRCC treated with sunitinib or sorafenib from 2007 to 2017 at Fudan University- and Hexi University-affiliated hospitals. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Multivariate regression analysis was used to evaluate predictors of PFS and OS. RESULTS: Low NLR (<2.85) and MLR (<.30) were strongly associated with increased PFS and OS. Multivariable analyses verified that the NLR and MLR were both independent prognostic factors. Additionally, the NLR was negatively correlated with CD8+ and CD4+ T-cell infiltration in tumors. CONCLUSION: In patients with mRCC treated with sunitinib and sorafenib, an NLR <2.85 and MLR <.30 was associated with superior PFS and OS, which may be related to the reduced lymphocytic infiltration of tumors.

Conservative treatment of urinary fistula: Case report.

Radical cystectomy is the gold standard treatment for muscular invasive bladder cancer. Bricker surgery is the most common technique used for urinary diversion; however, troublesome complications such as postoperative anastomotic stenosis or fistula may occur. The case of a patient who had a urinary fistula after Bricker surgery performed at our hospital, is described. The patient was successfully treated with continuous double-cannula negative-pressure drainage and avoided a second surgery. The patient recovered well and is on regular follow-up. This case highlights the importance of timely and relevant treatment for patients with postoperative urinary fistula to avoid more invasive surgery.

A novel lncRNA ARST represses glioma progression by inhibiting ALDOA-mediated actin cytoskeleton integrity.

BACKGROUND: Glioma is one of the most aggressive malignant brain tumors that is characterized with inevitably infiltrative growth and poor prognosis. ARST is a novel lncRNA whose expression level is significantly decreased in the patients with glioblastoma multiforme. However, the exact mechanisms of ARST in gliomagenesis are largely unknown. METHODS: The expressions of ARST in the glioma samples and cell lines were analyzed by qRT-PCR. FISH was utilized to detect the distribution of ARST in the glioma cells. CCK-8, EdU and flow cytometry were used to examine cellular viability, proliferation and apoptosis. Transwell and wound-healing assays were performed to determine the migratory and invasive abilities of the cells. Intracranial tumorigenesis models were established to explore the roles of ARST in vivo. RNA pulldown assay was used to examine proteins that bound to ARST. The activities of key enzymes in the glycolysis and production of lactate acid were measured by colorimetry. In addition, RIP, Co-IP, western blot and immunofluorescence were used to investigate the interaction and regulation between ARST, F-actin, ALDOA and cofilin. RESULTS: In this study, we reported that ARST was downregulated in the gliomas. Overexpression of ARST in the glioma cells significantly suppressed various cellular vital abilities such as cell growth, proliferation, migration and invasion. The tumorigenic capacity of these cells in vivo was reduced as well. We further demonstrated that the tumor suppressive effects of ARST could be mediated by a direct binding to a glycolytic enzyme aldolase A (ALDOA), which together with cofilin, keeping the polymerization and depolymerization of actin filaments in an orderly dynamic equilibrium. Upregulation of ARST interrupted the interaction between ALDOA and actin cytoskeleton, which led to a rapid cofilin-dependent loss of F-actin stress fibers. CONCLUSIONS: Taken together, it is concluded that ARST performs its function via a non-metabolic pathway associated with ALDOA, which otherwise modifies the morphology and invasive properties of the glioma cells. This has added new perspective to its role in tumorigenesis, thus providing potential target for glioma diagnosis, therapy, and prognosis.

Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors.

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.

Design, synthesis, and biological activity of new endomorphin analogs with multi-site modifications.

Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of [(2-furyl)Map4]EMs. The combination of [(2-furyl)Map4]EMs with D-Arg2 or D-Cit2 yielded analogs with enhanced binding affinity to the µ-opioid receptor (MOR) and increased stability against enzymatic degradation (t1/2 > 300 min). However, the agonistic activities of these analogs toward MOR were slightly reduced. Similar to morphine, peripheral administration of the analog [D-Cit2, (2-furyl)Map4]EM-1 (10) significantly inhibited the pain behavior of mice in multiple pain models. In addition, this EM-1 analog was associated with reduced tolerance, less effect on gastrointestinal mobility, and no significant motor impairment. Compared to natural EMs, the EM analogs synthesized herein had enhanced metabolic stability, bioavailability, and analgesic properties.

MEL endomorphins act as potent inflammatory analgesics with the inhibition of activated non-neuronal cells and modulation of pro-inflammatory cytokines.

Effective treatment of inflammatory pain is a major clinical concern for both patients and physicians. Traditional analgesics such as morphine and coxibs are not effective in all patients and have various unwanted side effects. Accumulating evidence has suggested that endomorphins (EMs), particularly EM-1, possess potent anti-inflammatory effects. However, poor bioavailability and low resistance to enzymatic degradation impede their direct application in the treatment of inflammation. A series of novel peptides based on the structure of EM-1, with lower undesired effects than their parent compounds, called MEL-EMs were discovered and synthetized in our preceding studies. Here, we selected two (MEL-0614 and MEL-N1606) to further investigate their anti-inflammatory effects. This work showed that MEL analogs exerted potent analgesic effects with the inhibition of activated glial cells and macrophages in a CFA-induced inflammatory pain model. Furthermore, multiple-dose administration of MEL analogs did not prolong CFA-induced chronic inflammatory pain, in contrast to morphine. Together, our findings revealed that MEL analogs may serve as effective candidates for chronic inflammation treatment.

MEL-N16: A Series of Novel Endomorphin Analogs with Good Analgesic Activity and a Favorable Side Effect Profile.

Opioid peptides are neuromodulators that bind to opioid receptors and reduce pain sensitivity. Endomorphins are among the most active endogenous opioid peptides, and they have good affinity and selectivity toward the µ opioid receptor. However, their clinical usage is hindered by their inability to cross the blood-brain barrier and their poor in vivo activity after peripheral injection. In order to overcome these defects, we have designed and synthesized a series of novel endomorphin analogs with multiple site modifications. Radioligand binding, cAMP accumulation, and ß-arrestin-2 recruitment assays were employed to determine the activity of synthesized endomorphin analogs toward opioid receptors. The blood-brain barrier permeability and antinociceptive effect of these analogs were determined in several rodent models of acute and persistent pain. In addition, the side effects of the analogs were examined. The radioligand binding assay and functional activity examination indicated that the MEL-N16 series of compounds were more active agonists against µ opioid receptor than were the parent peptides. Notably, the analogs displayed biased downstream signaling toward G-protein pathways over ß-arrestin-2 recruitment. The analogs showed highly potent antinociceptive effects in the tested nociceptive models. In comparison with endomorphins, the synthesized analogs were better able to penetrate the blood-brain barrier and exerted their pain regulatory activity in the central nervous system after peripheral injection. These analogs also have lower tendency to cause side effects than morphine does at similar or equal antinociceptive doses. The MEL-N16 compounds have highly potent and efficacious analgesic effects in various pain models with a favorable side effect profile.

Structure-constrained endomorphin analogs display differential antinociceptive mechanisms in mice after spinal administration.

We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the µ opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and ß-funaltrexamine (ß-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP. Antinociception induced by analog 2 through 4 was not reversed by δ opioid receptor (DOP) or κ opioid receptor (KOP) antagonist; antibodies against dynorphin-A (1-17), dynorphin-B (1-13), and Leu5/Met5-enkephalin had no impact on the antinociceptive effects of these analogs. In contrast, antinociceptive effects induced by a spinal injection of the fluorine substituted analog 1 were significantly reversed by KOP antagonism. Furthermore, intrathecal pretreatment with antibodies against dynorphin-B (1-13) attenuated the antinociceptive effect of analog 1. These results indicate that the antinociceptive activity exerted by intrathecally-administered analog 1 is mediated, in part, through KOP with increased release of dynorphin-B (1-13). The chemical modifications used in the present study may serve as a useful tool to gain insight into the mechanisms of endomorphins activity.

Diagnostic value of serum squamous cell carcinoma antigen for hepatocellular carcinoma: a systematic review and meta-analysis.

The aim of this study was to ascertain the diagnostic value of serum squamous cell carcinoma antigen (SCCA) and SCCA-IgM for hepatocellular carcinoma (HCC). After a comprehensive search of PubMed and Web of Science databases, we identified eligible studies on the diagnostic value serum SCCAs for HCC. The quality of the eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool. The overall diagnostic value of SCCAs for HCC was pooled using a bivariate model. Twelve studies were included in this systematic review and meta-analysis. The pooled sensitivities for SCCA and SCCA-IgM were 0.61 (95% confidence interval [CI], 0.37-0.81) and 0.70 (95% CI, 0.55-0.82), respectively. The corresponding specificities were 0.80 (95% CI, 0.52-0.94) and 0.62 (95% CI, 0.51-0.72), respectively. The areas under summary receiver operating characteristic (sROC) curves for SCCA and SCCA-IgM were 0.76 (95% CI, 0.72-0.80) and 0.70 (95% CI, 0.66-0.74), respectively. Major design deficiencies of the included studies were two-gate design and partial verification bias. Therefore, we concluded that both serum SCCA and SCCA-IgM have a fair diagnostic value for HCC.

GRIM-19 opposes reprogramming of glioblastoma cell metabolism via HIF1α destabilization.

The metabolism that sustains cancer cells is adapted preferentially to glycolysis, even under aerobic conditions (Warburg effect). This effect was one of the first alterations in cancer cells recognized as conferring a survival advantage. In this study, we show that gene associated with retinoid-interferon-induced mortality-19 (GRIM-19), which was previously identified as a tumor suppressor protein associated with growth inhibition and cell apoptosis, contributes to the switch between oxidative and glycolytic pathways. In parallel to this, vascular endothelial growth factor, which promotes neovascularization, is also regulated. We have identified hypoxia-inducible factor 1α (HIF1α) as the downstream factor of GRIM-19 in human glioblastoma cell lines. Downregulation of GRIM-19 promotes HIF1α synthesis in a STAT3-dependent manner, which acts as a potential competitive inhibitor for von Hippel-Lindau (pVHL)-HIF1α interaction, and thereby prevents HIF1α from pVHL-mediated ubiquitination and proteasomal degradation. Taken together, it is concluded that GRIM-19, a potential tumor suppressor gene, performs its function in part via regulating glioblastoma metabolic reprogramming through STAT3-HIF1α signaling axis, and this has added new perspective to its role in tumorigenesis, thus providing potential strategies for tumor metabolic therapy.