Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

Metabolic and pharmacological profiling of Penicillium claviforme by a combination of experimental and bioinformatic approaches

BackgroundPenicillium produces a wide range of structurally diverse metabolites with significant pharmacological impacts in medicine and agriculture. For the first time, a complete metabolome of Penicillium claviforme (P. claviforme) (FBP-DNA-1205) was studied alongside pharmacological research in this study.MethodsThe metabolic profile of P. claviforme fermented on Potato Dextrose Broth (PDB) was investigated in this work. The complete metabolomics studies of fungus were performed using GC-MS and LC-MS-QTOF techniques. An in vitro model was utilised to study the cytotoxic and antioxidant activities, while an in vivo model was employed to investigate the antinociceptive and acute toxicity activities. Molecular Operating Environment (MOE) software was used for molecular docking analysis.ResultsGC-MS study showed the presence of alkanes, fatty acids, esters, azo and alcoholic compounds. Maculosin, obtain, phalluside, quinoline, 4,4’-diaminostilbene, funaltrexamine, amobarbital, and fraxetin were among the secondary metabolites identified using the LC-MS-QTOF technique. The n-hexane fraction of P. claviforme displayed significant cytotoxic activity in vitro, with an LD50 value of 92.22 µgml⁻¹. The antinociceptive effects in vivo were dose-dependent significantly (p < .001). Interestingly, during the 72 h of investigation, no acute toxicity was demonstrated. In addition, a docking study of tentatively identified metabolites against the inflammatory enzyme (COX-2) supported the antinociceptive effect in an in silico model.ConclusionMetabolic profile of P. claviforme shows the presence of biologically relevant compounds in ethyl acetate extract. In addition, P. claviforme exhibits substantial antioxidant and cytotoxic activities in an in vitro model as well as antinociceptive activity in an in vivo model. The antinociceptive action is also supported by a molecular docking study. This research has opened up new possibilities in the disciplines of mycology, agriculture, and pharmaceutics.

Key messages

• The first time explored complete metabolome through GC-MS and LC-MS-QTOF.
• Both in vivo & in vitro pharmacological investigation of P. claviforme.
• In silico molecular docking of LC-MS-QTOF metabolites.

     

Performance of Microchannel Heat Sink Made of Silicon Material with the Two-Sided Wedge

New designs of the microchannel with a two-sided wedge shape at the base were studied numerically. Five different wedge angles ranging from 3° to 15° were incorporated into the microchannel design. Simulation of this novel microchannel was carried out using Computational Fluid Dynamics (CFD). Three-dimensional models of the microchannel heat sink were created, discretized, and based on Navier–Stokes and energy equations; laminar numerical solutions were obtained for heat transfer and pressure drop. Flow characteristics of water as coolant in a microchannel were studied. It was observed that numerical results are in good agreement with experimental results. It was found that the Nusselt number and friction factor are significantly varied with the increase in Reynolds number. The Nusselt number varies in the following ranges of 5.963–8.521, 5.986–8.550, 6.009–8.568, 6.040–8.609, and 6.078–8.644 at 3°, 6°, 9°, 12°, and 15°, respectively. The microchannel with a wedge angle of 15° was found to be better in terms of Nusselt number and thermo-hydraulic performance. The enhancement in the Nusselt number is found as 1.017–1.036 for a wedge angle of 15°; however, friction factors do not show the perceptible values at distinct values of wedge angle. Moreover, the thermo-hydraulic performance parameters (THPP) were evaluated and found to be maximum in the range of 1.027–1.045 for a wedge angle of 15°. However, minimum THPP was found in the range of 1.005–1.0185 for a wedge angle of 3°.     

Surface-engineered liposomes for dual-drug delivery targeting strategy against methicillin-resistant Staphylococcus aureus (MRSA)

This study focused on the encapsulation of vancomycin(VAN) into liposomes coated with a red blood cell membrane with a targeting ligand, daptomycin–polyethylene glycol–1,2-distearoyl-sn-glycero-3-phosphoethanolamine, formed by conjugation of DAPT and Nhydroxysuccinimidyl-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine.This formulation is capable of providing controlled and targeted drug delivery to the bacterial cytoplasm. We performed MALDI-TOF, NMR and FTIR analyses to conf...     

Factors predicting success of emergency extracorporeal shockwave lithotripsy (eESWL) in ureteric calculi—a single centre experience from the United Kingdom (UK)

Few studies show that “emergency extracorporeal shockwave lithotripsy (eESWL)” reduces the incidence of ureteroscopy in patients with ureteric calculi. We assess success of eESWL and look to study and identify factors which predict successful outcome. We retrospectively studied patients presenting with their first episode of ureteric colic undergoing eESWL (within 72 h of presentation) over a 5-year period. Patient’s age, gender, stone size and location, time between presentation and ESWL, number of shock waves and ESWL sessions, and Hounsfield units (HU) were recorded. 97 patients (mean age 40 years; 76 males, 21 females) were included. 71 patients were stone free after eESWL (73.2 %) (group 1) and 26 patients failed treatment and proceeded to ureteroscopy (group 2). The two groups were well matched for age and gender. Mean stone size in group 1 and 2 was 6.4 mm and 7.7 mm, respectively, (p = 0.00141). Stone location was 34, 21, and 16 in upper, middle and lower ureter in group 1 compared to 11, 5, and 10 in group 2, respectively. Mean HU in group 1 was 480 and 612 in group 2 (p value 0.0036). In group 2, significantly, more patients received treatment after 24 h compared with group 1 (38 vs 22.5 %). The number of shock waves, maximal intensity, and ESWL sessions were not significantly different in the two groups. No complications were noted. eESWL is safe and effective in patients with ureteric colic. Stone size and Hounsfield units are important factors in predicting success. Early treatment (≤24 h) minimizes stone impaction and increases the success rate of ESWL.