Inactive ERBB Receptors Cooperate With Reactive Oxygen Species To Suppress Cancer Progression

The ERBB receptors are a family of heterodimerization partners capable of driving transformation and metastasis. While the therapeutic targeting of single receptors has proven efficacious, optimal targeting of this receptor family should target all oncogenic members simultaneously. The juxtamembrane domains of ERBB1, ERBB2, and ERBB3 are highly conserved and control various aspects of ERBB-dependent biology. In an effort to block those functions, we have targeted this domain with decoy peptides synthesized in tandem with a cell-penetrating peptide, termed EJ1. Treatment with EJ1 induces cell death, promotes the formation of inactive ERBB multimers, and results in simultaneous reduction of ERBB1, ERBB2, and ERBB3 activation. Treatment also results in the activation of myosin light chain–dependent cell blebbing while inactivating CaMKII signaling, coincident with the induction of cell death. EJ1 also directly translocates to mitochondria, correlating with a loss of mitochondrial membrane potential and production of reactive oxygen species. Finally, treatment of a mouse model of breast cancer with EJ1 results in the inhibition of tumor growth and metastasis without associated toxicities in normal cells. Overall, these data demonstrate that a portion of the ERBB jxm domain, when used as an intracellular decoy, can inhibit tumor growth and metastasis, representing a novel anticancer therapeutic.     

Effect of ethanolic extracts of Justicia neesii Ramam. against experimental models of pain and pyrexia

Objective:The main objective of this study is to evaluate the analgesic and anti-pyretic activities of ethanolic extracts of Justicia neesii Ramam. by different experimental models.Results:In the hot plate model 400 mg/kg p.o. dose of J. neesii has shown its maximal effect at 3 h. The results are significant (P < 0.05) and comparable to the values of standard drug pentazocine (30 mg/kg i.p.). In acetic acid induced writhing model 400 mg/kg p.o. of plant extracts have shown highly significant activity (P < 0.001) and better than standard drug indomethacin (10 mg/kg p.o.). The 400 mg/kg p.o. dose of plant extract has given significant results against both yeast induced pyrexia and TAB vaccine induced pyrexia (P< 0.01 and 0.05 respectively). These values are comparable to that of paracetamol 100 mg/kg p.o. standard dose.Conclusion:This study shows that the ethanol extract of J. neesii has significant analgesic and antipyretic activity.KEY WORDS: Brewer''s yeast, hot plate, pyrexia, TAB vaccine, writhing     

Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes

AIM: To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS: This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION: Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.     

Piroxicam gel, compared to EMLA cream is associated with less pain after venous cannulation in volunteers

PURPOSE: To evaluate and compare the analgesic efficacy and anti-inflammatory effects of topical piroxicam gel vs eutectic mixture of local anesthetic (EMLA) cream applied to the peripheral venous cannulation site in adult volunteers. METHODS: Piroxicam gel and EMLA cream were randomly applied on the dorsum of the right and left hand of ten volunteers who acted as their own control. A venous cannula was inserted (no iv infusion) and removed after one hour. Pain scores and signs of inflammation were noted at the cannulation site up to 48 hr. RESULTS: Pain scores with piroxicam gel were higher on cannulation and on advancement of the cannula (P < 0.05). Thereafter, pain scores were significantly higher with EMLA (P < 0.05). Blanching was present at all the peripheral venous sites treated with EMLA cream. Signs of inflammation (erythema, edema) were not more frequent with EMLA than with piroxicam (P > 0.05). Induration was more frequent with EMLA at six hours. CONCLUSION: In volunteers EMLA cream is associated with less pain on cannulation and cannula advancement compared to piroxicam gel. Topical application of piroxicam gel before peripheral venous cannulation alleviates pain and, possibly, inflammation in the period subsequent to cannulation itself.     

Dual infections of mice: Visceral larva migrans and sublethal infection with Japanese encephalitis virus

Experiments in 3 weeks old albino mice with Toxocara canis and sublethal infection with JE virus established a marked synergestic effect in dually infected mice. The results are discussed to indicate the possible rôle of visceral larva migrans in creating explosive outbreaks of “acute encephalopathy syndrome” in individuals having simultaneous infection with a virus (es) which, alone, might produce only mild illness. The nature of the possible mechanisms involved yet remains to be understood.