Therapeutic monoclonal antibodies and antibody products: Current practices and development in multiple myeloma

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation

An Experimental Study and Database for Tip Vortex Flow From an Airfoil

An experimental investigation of tip vortices from a NACA0012 airfoil is conducted in a low-speed wind tunnel at a chord Reynolds number (Rc) of 410(exp 4 ). Data for the stationary airfoil at various angles of attack (alpha) are first discussed. Detailed flow-field surveys are done for two cases: alpha = 10deg with attached flow and alpha = 25deg with massive flow separation. Data include mean velocity, streamwise vorticity, and turbulent stresses at various streamwise locations. For all cases, the vortex core is seen to involve a mean velocity deficit. The deficits in these cases trace to the airfoil wake, part of which gets wrapped up by the tip vortex. Comparison with data from the literature suggests that with increasing Rc, the deficit turns into an excess, with the transition occurring in the approximate Rc range of 210(exp 5) to 510(exp 5). Survey results for various shapes of the airfoil wingtip are then presented. The shapes include square and rounded ends and a number of winglet designs. Finally, data under sinusoidal pitching condition, for the airfoil with square ends, are documented. All pitching cases pertain to a mean alpha = 15deg, while the amplitude and frequency are varied. Amplitudes of +/-5deg, +/-10deg, and +/-15deg and reduced frequencies k = 0.08, 0.2, and 0.33 are covered. Digital records of all data and some of the hardware design are made available on a supplemental CD with the electronic version of the paper for those interested in numerical simulation

Replacing Sugar by Date Syrup in Gaz and Investigation of Texture Properties

Date Syrup is a natural sweetener that is suitable replacement for sugar in food stuffs formulation. In this Research Amounts of 25-100 percent of sugar in Gaz formulation were replaced with date syrup and to study effect of its use in product formulation, characteristics of texture, color and sensory analyse of treatments were investigated. Statistical analyse of data was also done by SPSS software and Dankan test. The results of this research showed that amount of used date syrup in formulation had a significant effect on color parameters (L*,a*,b*), texture characteristics and sensory analyse of samples. By increase of date syrup in Gaz formulation, samples texture became softer than control sample and yellowness and redness index of samples were increasedDoi: DOI: 10.12777/ijse.6.1.11-15 [How to cite this article: Shafiei, Z., Hojjatoleslami, M., Soha, S., and Shariati, M.A. 2014. The Influence of Malt Extraction Adding to UF Fresh Low Fat Cheese on Its Textural Properties. International Journal of Science and Engineering, 6(1):57-60. Doi: 10.12777/ijse.6.1.11-1

Selected amino acid changes in HIV-1 subtype-C gp41 are associated with specific gp120(V3) signatures in the regulation of co-receptor usage

The majority of studies have characterized the tropism of HIV-1 subtype-B isolates, but little is known about the determinants of tropism in other subtypes. So, the goal of the present study was to genetically characterize the envelope of viral proteins in terms of co-receptor usage by analyzing 356 full-length env sequences derived from HIV-1 subtype-C infected individuals. The co-receptor usage of V3 sequences was inferred by using the Geno2Pheno and PSSM algorithms, and also analyzed to the "11/25 rule". All reported env sequences were also analyzed with regard to N-linked glycosylation sites, net charge and hydrophilicity, as well as the binomial correlation phi coefficient to assess covariation among gp120(V3) and gp41 signatures and the average linkage hierarchical agglomerative clustering were also performed. Among env sequences present in Los Alamos Database, 255 and 101 sequences predicted as CCR5 and CXCR4 were selected, respectively. The classical V3 signatures at positions 11 and 25, and other specific V3 and gp41 amino acid changes were found statistically associated with different co-receptor usage. Furthermore, several statistically significant associations between V3 and gp41 signatures were also observed. The dendrogram topology showed a cluster associated with CCR5-usage composed by five gp41 mutated positions, A22V, R133M, E136G, N140L, and N166Q that clustered with T2V(V3) and G24T(V3) (bootstrap=1). Conversely, a heterogeneous cluster with CXCR4-usage, involving S11GR(V3), 13-14insIG/LG(V3), P16RQ(V3), Q18KR(V3), F20ILV(V3), D25KRQ(V3), Q32KR(V3) along with A30T(gp41), S107N(gp41), D148E(gp41), A189S(gp41) was identified (bootstrap=0.86). Our results show that as observed for HIV-1 subtype-B, also in subtype-C specific and different gp41 and gp120V3 amino acid changes are associated individually or together with CXCR4 and/or CCR5 usage. These findings strengthen previous observations that determinants of tropism may also reside in the gp41 protein

Photodynamic therapy offers a novel approach to managing miltefosine-resistant cutaneous leishmaniasis

Funding: Engineering and Physical Sciences Research Council of the UK (grants EP/R035164/1 and EP/L015110/1) and the Scottish Funding Council (ODA GCRF fund grant SFC/AN/12/2017).Cutaneous leishmaniasis (CL) is a neglected disease caused by Leishmania parasites. The oral drug miltefosine is effective, but there is a growing problem of drug resistance, which has led to increasing treatment failure rates and relapse of infections. Photodynamic therapy (PDT) combines a light source and a photoactive drug to promote cell death by oxidative stress. Although PDT is effective against several pathogens, its use against drug resistant Leishmania parasites remains unexplored. Herein, we investigated the potential of organic light-emitting diodes (OLEDs) as wearable light sources, which would enable at-home use or ambulatory treatment of CL. We also assessed its impact on combating miltefosine resistance in Leishmania amazonensis-induced CL in mice. Thein vitro activity of OLEDs combined with 1,9-dimethyl-methylene blue (DMMB) (OLED-PDT) was evaluated against wild-type and miltefosine-resistant L. amazonensis strains in promastigote (EC50 = 0.034 μM for both strains) and amastigote forms (EC50 = 0.052 μM and 0.077 μM, respectively). Cytotoxicity in macrophages and fibroblasts was also evaluated. In vivo, we investigated the potential of OLED-PDT in combination with miltefosine using different protocols. Our results demonstrate that OLED-PDT is effective in killing both strains of L. amazonensis by increasing reactive oxygen species and stimulating nitric oxide production. Moreover, OLED-PDT showed great antileishmanial activity in vivo, allowing the reduction of miltefosine dose by half in infected mice using a light dose of 7.8 J/cm2 and 1.5 μM DMMB concentration. In conclusion, OLED-PDT emerges as a new avenue for at-home care and allows a combination therapy to overcome drug resistance in cutaneous leishmaniasis.Peer reviewe

Solvent-free synthesis of xanthene derivatives by Preyssler type heteropolyacid

Dimedone reacted with aromatic aldehydes and 3,4-methylenedioxyphenol or β-naphthol in the presence of a catalytic amount of Preyssler type heteropolyacid, H14[NaP5W30O110], as a green and reusable catalyst under solvent-free conditions to form a variety of  new xanthene derivatives in very good  yields.KEY WORDS: Xanthene derivatives, Solvent-free synthesis, Preyssler type heteropolyacid, 3,4-Methylene dioxyphenol, β-Naphthol, Three-component one-pot reactions Bull. Chem. Soc. Ethiop. 2011, 25(3), 399-406

Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia:a study in rats

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9-11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage