A renal cell carcinoma with EWSR1-TFE3 fusion gene.

Both EWSR1 and TFE3 are well-known oncogenes. EWSR1 encodes an RNA-binding protein involved in multiple soft tissue tumors, including Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor, soft tissue clear cell sarcoma (malignant melanoma of soft parts), extraskeletal myxoid chondrosarcoma, and myxoid liposarcomas. TFE3 regulates both Golgi and lysosomal homeostasis and is rearranged in renal cell carcinoma (RCC), alveolar soft part sarcoma, epithelioid hemangioendothelioma, and perivascular epitheloid cell tumors (PEComas). In this report, we found a rare case of RCC with a fusion between 5' EWSR1 and 3' TFE3. The fusion product retained most functional motifs of TFE3. The oncogenic mechanism likely involves TFE3 overexpression through its juxtaposition with the regulatory elements of EWSR1 and its translocation to the nucleus, resulting in the deregulation of Golgi and lysosomal homeostasis. This is a second case of RCC containing EWSR1-TFE3 fusion.

Chronic stress influences nociceptive sensitivity of female rats in an estrous cycle-dependent manner.

Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.SUMMARYOur studies showed that chronic stress increased nociceptive sensitivity of female rats. Furthermore females had different stress-induced pain responses in different estrous phases: mechanical hyperalgesia in proestrus and estrus, formalin-evoked acute hyperalgesia in metestrus and diestrus.

Duloxetine for pain in fibromyalgia in adults: a systematic review and a meta-analysis.

Objectives: The objective of this systematic review was to assess the analgesic efficacy of duloxetine (DLX) for fibromyalgia (FM) and find out which dosage between 60 mg/d DLX and 120 mg/d DLX was more suitable for clinical application.Methods: A systematic search through multiple databases (Cochrane Central Register of Controlled Trials (CENTRAL), ProQuest, PubMed) was conducted from 2000 until 7 March 2019. All steps were performed by two or more independent reviewers. The meta-analysis was performed to report the effects of DLX on pain reduction and its accompanied adverse events.Results: This meta-analysis, including seven studies with 2642 FM patients, demonstrated that DLX could produce greater pain relief in FM than placebo (standardized mean difference (SMD) -0.26; 95% confidence interval (CI) -0.37 to -0.16). The risk ratio (RR) of at least 30% pain relief was 1.31 (95% CI 1.19 to 1.44); the RR of at least 50% pain relief was 1.46 (95% CI 1.28 to 1.67). However, the patients with DLX who suffered adverse events were more common than the ones with placebo (RR 1.17, 95% CI 1.12 to 1.23). The withdrawal effect included adverse event withdrawal and lack of efficacy withdrawal. The subgroup analyses of withdrawal effects demonstrated that 120 mg/d DLX had a higher incidence (RR 0.96, 95% CI 0.80 to 1.15) than 60 mg/d DLX (RR 0.77, 95% CI 0.63 to 0.93).Conclusions: In general, DLX was a great choice for pain relief in FM. Moreover, 60 mg/d DLX produced less withdrawal effects than 120 mg/d DLX. HighlightsFibromyalgia (FM) is a chronic condition of unknown aetiology, characterized by widespread pain and often associated with other symptoms.Duloxetine (DLX), a serotonin norepinephrine (noradrenaline) reuptake inhibitor (SNRI), is used to treat FM in many countries.DLX can produce greater pain relief in FM than placebo.DLX can bring about more adverse events than placebo.60 mg/d DLX produces less withdrawal than 120 mg/d DLX for FM patients.

Hydrogen saline prevents selenite-induced cataract in rats.

PURPOSE: The aim of this study was to investigate the potential antioxidative effect and mechanism for the protective effects of hydrogen saline on selenite-induced cataract in rats. METHODS: Sprague-Dawley rat pups were divided into the following groups: control (Group A), selenite induced (Group B), and selenite plus hydrogen saline treated (Group C). Rat pups in Groups B and C received a single subcutaneous injection of sodium selenite (25 µmol/kg bodyweight) on postnatal day 12. Group C also received an intraperitoneal injection of H2 saline (5 ml/kg bodyweight) daily from postnatal day 8 to postnatal day 17. The development of cataract was assessed weekly by slit-lamp examination for 2 weeks. After sacrifice, extricated lenses were analyzed for activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of malondialdehyde, reduced glutathione (GSH), and total sulfhydryl contents. RESULTS: The magnitude of lens opacification in Group B was significantly higher than in Group A (p<0.05), while Group C had less opacification than Group B (p<0.05). Compared with Group B, the mean activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, levels of GSH, and total sulfhydryl contents were higher, whereas the level of malondialdehyde was lower following treatment with hydrogen saline(p<0.05). CONCLUSIONS: This is an initial report showing that hydrogen saline can prevent selenite-induced cataract in rats. It acts via maintaining antioxidant enzymes and GSH, protecting the sulfhydryl group, and inhibiting lipid peroxidation.

Oral delivery of dsHvlwr is a feasible method for managing the pest Henosepilachna vigintioctopunctata (Coleoptera: Coccinellidae).

RNA interference (RNAi) techniques have emerged as powerful tools that facilitate development of novel management strategies for insect pests, such as Henosepilachna vigintioctopunctata (Coleoptera: Coccinellidae), which is a major pest of solanaceous plants in Asia. In this study, the potential of oral delivery of in vitro-synthesized and bacterially expressed double-stranded H. vigintioctopunctata lesswright (lwr) gene (dsHvlwr) to manage of H. vigintioctopunctata was investigated. Our results showed that the gene Hvlwr had a 480-bp open reading frame and encoded a 160-amino acid protein. Hvlwr expression levels were greater in the fat body than other tissue types. Hvlwr silencing led to greater H. vigintioctopunctata mortality rates and appeared to be time- and partially dose-dependent, likely as a result of the number of hemocytes increasing with dsRNA concentration, but decreasing with time. Bacterially expressed dsHvlwr that was applied to leaf discs caused 88%, 66%, and 36% mortality in 1st instars, 3rd instars, and adults after 10, 10, and 14 d, respectively; when applied to living plants, there was greater mortality in 1st and 3rd instars, but there was no effect on adults. Furthermore, dsHvlwr led to improved plant protection against H. vigintioctopunctata. Our study shows an effective dietary RNAi response in H. vigintioctopunctata and that Hvlwr is a promising RNAi target gene for control of this pest species.

MK-801 changes the role of glutamic acid on modulation of algesia in nucleus accumbens.

Dizocilpine maleate (MK-801) causes the blockage of the glutamic acid (Glu) receptors in the central nervous system that are involved in pain transmission. However, the mechanism of action of MK-801 in pain-related neurons is not clear, and it is still unknown whether Glu is involved in the modulation of this processing. This study examines the effect of MK-801, Glu on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the nucleus accumbens (NAc) of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in NAc were recorded by a glass microelectrode. Our results revealed that the lateral ventricle injection of Glu increased the discharged frequency and shortened the discharged latency of PEN, and decreased the discharged frequency and prolonged the discharged inhibitory duration (ID) of PIN in NAc of rats evoked by the noxious stimulation, while intra-NAc administration of MK-801 produced the opposite response. On the basis of above findings we can deduce that Glu, MK-801 and N-methyl-D-aspartate (NMDA) receptor are involved in the modulation of nociceptive information transmission in NAc.

Cholecystokinin-8 antagonizes electroacupuncture analgesia through its B receptor in the caudate nucleus.

OBJECTIVES: The analgesic effect of electroacupuncture (EA) stimulation has been proved. However, its mechanism of action is not clear. It has been well-known that cholecystokinin-8 (CCK-8) is a neuropeptide which is mainly related to the mediation of pain. The caudate nucleus was selected to determine if the release of CCK and the neural activity in this nucleus were involved in producing EA analgesia. MATERIALS AND METHODS: Radiant heat focused on the rat-tail was used as the noxious stimulus. The pain threshold of rats was measured by tail-flick latency (TFL). EA stimulation at the bilateral Zusanli (ST 36) acupoints of rats was used to investigate the effects of EA analgesia. The electrical activities of pain-excited neurons (PEN) and pain-inhibited neurons (PIN) in the caudate nucleus were recorded with a glass microelectrode. The present study examined the antagonistic effects of the intracerebral ventricular injection of CCK-8 on EA analgesia and reversing effects of CCK-B receptor antagonist (L-365,260) injection into the caudate nucleus on CCK-8. RESULTS: The radiant heat focused on the tail of rats caused an increase in the evoked discharge of PEN and a reduction in the evoked discharge of PIN. EA stimulation at the bilateral ST 36 acupoints of rats resulted in the inhibition of PEN, the potentiation of PIN, and prolongation of TFL. The analgesic effect of EA was antagonized when CCK-8 was injected into the intracerebral ventricle of rats. The antagonistic effect of CCK-8 on EA analgesia was reversed by injection of CCK-B receptor antagonist (L-365,260) into the caudate nucleus of rats. CONCLUSIONS: Our results suggest that CCK-8 antagonize EA analgesia through its B receptor.

Rapid Molecular Response to Dasatinib in a Pediatric Relapsed Acute Lymphoblastic Leukemia With NCOR1-LYN Fusion.

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with high rates of treatment failure and poor outcome. Activation of ABL/Src family kinases is found in ~10% of Ph-like ALL, which can be therapeutically targeted by tyrosine kinase inhibitors. LYN is a member of the ABL/Src-tyrosine kinase family. Somatic LYN rearrangements are found in 5 cases of hematopoietic malignancies so far, although none of them were treated with tyrosine kinase inhibitors. Case presentation: A 6-year-old boy with relapsed B-ALL had no response to reinduction chemotherapy. He was then treated with the ABL1 tyrosine kinase inhibitor dasatinib and achieved complete remission within 2 weeks. Haploidentical allogenic stem cell transplantation (allo-HSCT) was subsequently performed and maintenance therapy with dasatinib initiated 8 weeks post-transplantation. He has been in minimal residual disease negative remission for 10 months after allo-HSCT. Result: His bone marrow karyotype showed a balanced translocation between chromosomes 8 and 17, leading to a NCOR1-LYN fusion gene confirmed with sequencing. Conclusion: Although LYN overexpression is described in many AML and B-ALL patients, intragenic LYN rearrangement is a rare event. For the first time, we present evidence that dasatinib is effective in treating a pediatric B-ALL with NCOR-LYN fusion.

Identification of STRBP as a Novel JAK2 Fusion Partner Gene in a Young Adult With Philadelphia Chromosome-Like B-Lymphoblastic Leukemia.

Philadelphia chromosome-like B-lymphoblastic leukemia (Ph-like ALL) describes a group of genetically heterogeneous, Ph-negative entities with high relapse rates and poor prognoses. A Janus-kinase-2 (JAK2) rearrangement has been reported in approximately 7% of Ph-like ALL patients whose therapeutic responses to JAK inhibitors have been studied in clinical trials. Here, we report a novel STRBP-JAK2 fusion gene in a 21-year-old woman with Ph-like ALL. Although a normal karyotype was observed, a hitherto unreported JAK2 rearrangement was detected cytogenetically. STRBP-JAK2 fusion was identified by RNA sequencing and validated by Sanger sequencing. The Ph-like ALL proved refractory to traditional induction chemotherapy combined with ruxolitinib. The patient consented to infusion of autologous chimeric antigen receptor (CAR) T cells against both CD19 and CD22, which induced morphologic remission. Haplo-identical stem cell transplantation was then performed; however, she suffered relapse at just one month after transplantation. The patient subsequently received donor lymphocyte infusion after which she achieved and maintained a minimal residual disease negative remission. However, she succumbed to grade IV graft-versus-host disease 7 months post-transplant. In conclusion, this report describes a novel STRBP-JAK2 gene fusion in a Ph-like ALL patient with a very aggressive disease course, which proved resistant to chemotherapy combined with ruxolitinib but sensitive to immunotherapy. Our study suggests that CAR T-cell therapy may be a viable option for this type of leukemia.

Astemizole protects against human umbilical vein endothelial cell injury induced by hydrogen peroxide via the p53 signaling pathway.

Astemizole has gained attention as an antineoplastic drug that targets important ion channels. The present study aimed to investigate the protective effects of astemizole against hydrogen peroxide (H2O2)­induced oxidative damage to human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated with astemizole (0.5 and 1 µM) for 12 h, then exposed to H2O2 (200 µM) for 12 h. Cell viability was measured using the MTT assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH­Px), reactive oxygen species (ROS) and apoptotic percentage were determined. Additionally, the protein expression of p53, p21Cip1/Waf1 and p16INK4a was measured by western blot analysis The results demonstrated that astemizole (0.5­1 µM) was able to significantly restore the viability of HUVECs under oxidative stress and scavenge intracellular ROS induced by H2O2. Astemizole also suppressed the production of lipid peroxides, such as MDA, and restored the activities of endogenous antioxidants, including SOD and GSH­Px, indicating that cell apoptosis may be inhibited. In addition, astemizole significantly increased p53, p21Cip1/Waf1 and p16INK4a protein expression. In conclusion, astemizole effectively protected endothelial cells against oxidative stress induced by H2O2, a function that may involve ROS/p53/p21Cip1/Waf1/ p16INK4a signaling pathways. The present study therefore served as a preliminary investigation into the ROS­protective effects of astemizole, and may pave the way for future studies into the development of this compound as a novel therapy for atherosclerosis.

Effect of acetylcholine receptors on the pain-related electrical activities in the hippocampal CA3 region of morphine-addicted rats.

OBJECTIVES: To determine the effect of acetylcholine (ACh), pilocarpine, and atropine on pain evoked responses of pain excited neurons (PEN) and pain inhibited neurons (PIN) in hippocampal CA3 region of morphine addicted rats. MATERIALS AND METHODS: Female Wistar rats, weighing between 230-260 g were used in this study. Morphine addicted rats were generated by subcutaneous injection of increasing concentrations of morphine hydrochloride for six days. Trains of electrical impulses applied to the sciatic nerve were used as noxious stimulation and the evoked electrical activities of PEN or PIN in hippocampal CA3 area were recorded using extracellular electrophysiological recording techniques in hippocampal slices. The effect of acetylcholine receptor stimulation by ACh, the muscarinic agonist pilocarpine, and the muscarinic antagonist atropine on the pain evoked responses of pain related electrical activities was analyzed in hippocampal CA3 area of morphine addicted rats. RESULTS: Intra-CA3 microinjection of ACh (2 µg/1 µl) or pilocarpine (2 µg/1 µl) decreased the discharge frequency and prolonged the firing latency of PEN, but increased the discharge frequency and shortened the firing inhibitory duration (ID) of PIN. The intra-CA3 administration of atropine (0.5 µg/1 µl) produced opposite effect. The peak activity of cholinergic modulators was 2 to 4 min later in morphine addicted rats compared to peak activity previously observed in normal rats. CONCLUSION: ACh dependent modulation of noxious stimulation exists in hippocampal CA3 area of morphine addicted rats. Morphine treatment may shift the sensitivity of pain related neurons towards a delayed response to muscarinergic neurotransmission in hippocampal CA3 region.

Acetylcholine plays an antinociceptive role by modulating pain-induced discharges of pain-related neurons in the caudate putamen of rats.

The caudate putamen (CPu) has been suggested to be involved in nociceptive modulation. Some neurotransmitters, including acetylcholine (ACh), participate in pain modulation in the central nervous system. However, the active mechanism of ACh on the pain-related neurons in the CPu remains unclear. This study aimed to investigate the effects of the cholinergic agonists ACh and pilocarpine and the muscarinic ACh receptor antagonist atropine on the pain-induced response of pain-related neurons in the CPu of Wistar rats. Trains of electrical impulses applied to the sciatic nerve of rat were used as the noxious stimulus. The electrical activities of pain-excited neurons (PENs) or pain-inhibited neurons (PINs) in the CPu were recorded by a glass microelectrode. Our results showed that an intra-CPu injection of 4 µg/2 µl ACh or pilocarpine decreased and increased the pain-induced discharge frequency in the PENs and PINs, respectively. Intra-CPu administration of 1 µg/2 µl atropine produced the opposite effect on these neurons. These findings indicate that ACh may play an analgesic role by affecting the electric activities of PENs and PINs, and the muscarinic pathway may be involved in the modulation of pain perception in the CPu.

Modulatory role of glutamic acid on the electrical activities of pain-related neurons in the hippocampal CA3 region.

Glutamic acid (Glu) participates in pain modulation of the central nervous system. The CA3 region of the hippocampal formation has been suggested to be involved in nociceptive perception. However, it is unknown whether Glu could modulate the electrical activities of pain-related neurons in the hippocampal CA3 region. The present study aimed to determine the effects of Glu and its receptor antagonist MK-801 in the pain-evoked response of both pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of normal rats. We used a train of electric impulses applied to the sciatic nerve as noxious stimulation. The electrical activities of either PENs or PINs in the hippocampal CA3 region were recorded by a glass microelectrode. The results revealed that intra-CA3 region microinjection of Glu (0.5 µg/1 µl) increased the evoked firing frequency and shortened the firing latency of PEN, while decreased the evoked firing frequency and prolonged the inhibitory duration of PIN in the hippocampal CA3 region of rat evoked by the noxious stimulation. Intra-CA3 region administration of MK-801 (0.25 µg/1 µl) produced the opposite response. These results suggest that Glu and its receptors in hippocampal CA3 region are involved in the modulation of nociceptive information transmission by affecting the electric activities of PENs and PINs.

Effects of norepinephrine on the electrical activities of pain-related neurons in the rat nucleus accumbens.

This study examined the effects of norepinephrine (NE) and phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the nucleus accumbens (NAc) of Wistar rats. Trains of electric pulses applied to the right sciatic nerve were used to provide noxious stimulation, and the discharges of PENs and PINs were recorded using a glass microelectrode. Our results revealed that in response to noxious stimulation, NE decreases the evoked discharge frequency of PENs and increases the evoked discharge frequency of PINs in the NAc of healthy rats, whereas phentolamine produced opposite responses. These results demonstrate that NE is involved in the modulation of nociceptive information transmission in the NAc.

Noradrenergic mechanism involved in the nociceptive modulation of nociceptive-related neurons in the caudate putamen.

Norepinephrine (NE) participates in pain modulation of the central nervous system. The caudate putamen (CPu) is one region of the basal ganglia that has been demonstrated to be involved in nociceptive perception. Our previous work has shown that microinjection of different doses of norepinephrine into the CPu produces opposing effects in the tail-flick latency (TFL) of rats. However, the mechanism of action of NE on the pain-related neurons in the CPu remains unclear. The present study examined the effects of NE and the alpha-adrenoceptor antagonist phentolamine on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the CPu of rats. Trains of electric impulses were used for noxious stimulation, and were applied to the sciatic nerve. The electrical activities of pain-related neurons in the CPu were recorded by a glass microelectrode. The results revealed that intra-CPu microinjection of NE (8microg/2microl) increased evoked firing frequency of PEN and shortened the firing latency, but decreased the evoked firing frequency of PIN and prolonged the inhibitory duration (ID). Intra-CPu administration of phentolamine (4microg/2microl) showed the opposite effects. The above results suggest that NE in the CPu modulates nociception by affecting the baseline firing rates of PENs and PINs.

Microinjection of different doses of norepinephrine into the caudate putamen produces opposing effects in rats.

It has been proven that norepinephrine (NE) regulates antinociception through its action on alpha-adrenoceptors located in brain nuclei, spinal cord, and peripheral organs. However, the supraspinal mechanism of noradrenergic pain modulation is controversial. The present study was aimed at investigating the nociceptive effects induced by injecting different doses of NE and phentolamine into the caudate putamen (CPU) of rats. The thermal pain threshold of the rats was measured by performing a tail-flick test. The tail-flick latency (TFL) was measured at 2-60 min after microinjection of the drugs. Our results revealed that the thermal pain threshold increased (long TFL) after the administration of a low dose of NE (2 microg/2 microl) and decreased (short TFL) after injection of a high dose of NE (8 microg/2 microl). In contrast, the pain threshold decreased after the administration of a low dose of phentolamine (1 microg/2 microl), while it increased after injection of a high dose of phentolamine (4 microg/2 microl). These results indicated that the injection of different doses of NE in the CPU of the rats produced opposite effects on the pain threshold, as determined by the tail-flick tests.

Stability of a rat model of prehepatic portal hypertension caused by partial ligation of the portal vein.

AIM: To study the stability of portal hypertension (PHT) caused by partial ligation of the portal vein ligation (PVL) in a rat model. METHODS: Thirty male adult Wistar rats were divided into two groups: 10 in Group I received a sham operation; and 20 in Group II received partial PVL. Portal vein pressure (PVP) was measured at four time periods: before ligation, 2 wk, 6 wk and 10 wk post-surgery. Portal venography, blood sampling and liver and spleen pathological examinations were conducted at 10 wk after surgery. RESULTS: The PVP was 9.15 +/- 0.58 cmH(2)O before ligation, and increased to 17.32 +/- 0.63 cmH(2)O 2 wk after PVL. By repeat measurement of the PVP in each rat, it was shown to remain elevated for 10 wk. There were no significant differences in the pressure measurements at 2 wk, 6 wk and 10 wk. Varices were found mainly in the mesenteric vein 2 wk after PVL, which were more obvious later, while these manifestations were similar at week 6 and week 10. Portal venography demonstrated the varices and collaterals. There was no significant change in liver pathology. The volume of the spleen was enlarged 2-fold after ligation, and the sinus of the spleen was enlarged due to congestion. Significant sinus endothelial cell proliferation was observed, but no evidence of hypersplenia was found on hemogram and biochemical examination. CONCLUSION: These findings suggest that a satisfactory prehepatic PHT rat model can be obtained by partial ligation of the portal vein, and this PHT rat model was stable for at least 10 wk.

L-365,260 reversed effect of sincalide against morphine on electrical and mechanical activities of rat duodenum in vitro.

AIM: To study the antagonism of sincalide (CCK-8) to the effect of morphine and its mechanism. METHODS: The electrical and mechanical activities of rat duodenum in vitro were recorded simultaneously. RESULTS: Acetylcholine (ACh, 300 nmol/L) increased the spike potential amplitude (SPA) and the number (SPN) of rat duodenum in vitro, followed by an increase of duodenal contraction amplitudes (CA). The SPA, SPN, and CA of duodenum in vitro were not obviously affected by injection of morphine (330 nmol/L), but it could selectively inhibit the potentiation of ACh. After administration of CCK-8 (0.7 nmol/L), the SPA, SPN, and CA of duodenal segment did not exhibit obvious changes. But CCK-8 could selectively antagonize the effects of morphine, ie, the SPA and SPN were increased again, followed by an increase of CA. CCK-B receptor antagonist L-365,260 (30 nmol/L) reversed the antagonism of CCK-8 to the effect of morphine. CONCLUSION: CCK-8 could selectively antagonize the effect of morphine which inhibited the potentiation of ACh on duodenal activities in vitro. The antagonistic effect of CCK-8 on morphine was mainly mediated by CCK-B receptor.