Double Relapsed and/or Refractory Multiple Myeloma: Clinical Outcomes and Real World Healthcare Costs

Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide, carries a poor prognosis. The healthcare costs of DRMM have not previously been reported. We analyzed detailed medical resource utilization (MRU) costs, drug costs and outcomes for 39 UK patients receiving standard DRMM therapy. Median OS in this cohort was 5.6 months. The mean cost of DRMM treatment plus MRU until death was £23,472 [range: £1,411–£90,262], split between drug costs £11,191 and other resource use costs £12,281. The cost per assumed quality-adjusted life year (QALY) during DRMM was £66,983. These data provide a standard of care comparison when evaluating the cost-effectiveness of new drugs in DRMM.     

Rapamycin inhibition of baculovirus recombinant (BVr) ribosomal protein S6 kinase (S6K1) is mediated by an event other than phosphorylation

Background

Ribosomal protein S6 kinase 1(S6K1) is an evolutionary conserved kinase that is activated in response to growth factors and viral stimuli to influence cellular growth and proliferation. This downstream effector of target of rapamycin (TOR) signaling cascade is known to be directly activated by TOR- kinase mediated hydrophobic motif (HM) phosphorylation at Threonine 412 (T412). Selective loss of this phosphorylation by inactivation of TOR kinase or activation/recruitment of a phosphatase has accordingly been implicated in mediating inhibition by rapamycin.

Findings

We present evidence that baculovirus driven expression of S6K1 in insect cells (Sf9) fails to activate the enzyme and instead renders it modestly active representing 4-6 folds less activity than its fully active mammalian counterpart. Contrary to the contention that viral infection activates TOR signaling pathway, we report that BVr enzyme fails to exhibit putative TOR dependent phosphorylation at the HM and the resultant phosphorylation at the activation loop (AL) of the enzyme, correlating with the level of activity observed. Surprisingly, the BVr enzyme continued to exhibit sensitivity to rapamycin that remained unaffected by mutations compromised for TOR phosphorylation (T412A) or deletions compromised for TOR binding (ΔNH _2-46/ΔCT₁₀₄).

Conclusions

These data together with the ability of the BVr enzyme to resist inactivation by phosphatases indicate that inhibition by rapamycin is not mediated by any phosphorylation event in general and TOR dependent phosphorylation in particular.     

Enhanced biosorption of mercury(II) and cadmium(II) by cold-induced hydrophobic exobiopolymer secreted from the psychrotroph <Emphasis Type="Italic">Pseudomonas fluorescens</Emphasis> BM07

The cells of psychrotrophic Pseudomonas fluorescens BM07 were found to secrete large amounts of exobiopolymer (EBP) composed of mainly hydrophobic (water insoluble) polypeptide(s) (as contain approximately 50 mol% hydrophobic amino acids, lacking cysteine residue) when grown on fructose containing limited M1 medium at the temperatures as low as 0-10 degrees C but trace amount at high (30 degrees C, optimum growth) temperature. Two types of nonliving BM07 cells (i.e., cells grown at 30 degrees C and 10 degrees C) as well as the freeze-dried EBP were compared for biosorption of mercury (Hg(II)) and cadmium (Cd(II)). The optimum adsorption pH was found 7 for Hg(II) but 6 for Cd(II), irrespective of the type of biomass. Equilibrium adsorption data well fitted the Langmuir adsorption model. The maximum adsorption (Q (max)) was 72.3, 97.4, and 286.2 mg Hg(II)/g dry biomass and 18.9, 27.0, and 61.5 mg Cd(II)/g dry biomass for cells grown at 30 degrees C and 10 degrees C and EBP, respectively, indicating major contribution of heavy metal adsorption by cold-induced EBP. Mercury(II) binding induced a significant shift of infrared (IR) amide I and II absorption of EBP whereas cadmium(II) binding showed only a very little shift. These IR shifts demonstrate that mercury(II) and cadmium(II) might have different binding sites in EBP, which was supported by X-ray diffraction and differential scanning calorimetric analysis and sorption results of chemically modified biomasses. This study implies that the psychrotrophs like BM07 strain may play an important role in the bioremediation of heavy metals in the temperate regions especially in the inactive cold season.     

Phenotypic and molecular identification of a novel thermophilic Anoxybacillus species: a lipase-producing bacterium isolated from a Malaysian hotspring

Eleven lipase-producing thermophilic bacteria strains were recently isolated from Kuala Woh Hot Spring, in Peninsular Malaysia. These strains have been qualitatively screened using Rhodamine B-olive oil plate agar. All strains showed lipase activity in the range of 0.56–2.62 U/ml. Their thermostabilities were then determined by incubation at 80°C for 30 min. Results showed that strain KW 6 and KW 12 produced relatively thermostable lipases, which retained 62 and 54% of their original activity, respectively. They were identified based on their morphological characteristics, biochemical tests and the Biolog system. Strain KW 12 showed exceptionally unique characteristics (over KW 6) being able to grow in a broad range of pH and temperature. It was further identified using 16S rRNA partial sequence analysis and the result of 16S rRNA partial sequence analysis identified KW 12 as Anoxybacillus kamchatkensis.     

Cost effective surface functionalization of silver nanoparticles for high yield immobilization of Aspergillus oryzae β-galactosidase and its application in lactose hydrolysis

The present study demonstrates synthesis, characterization and surface functionalization of silver nanoparticles (AgNPs) via glutaraldehyde for high yield immobilization of Aspergillus oryzae β-galactosidase. Soluble β-galactosidase (SβG), enzyme adsorbed on unmodified AgNPs (UβG) and surface modified AgNPs (MβG) showed same pH-optima at pH 4.5. However, it was observed that MβG exhibited enhanced pH stability toward acidic and alkaline sides, and increased temperature resistance as compared to SβG and UβG. Michaelis constant, K_m was increased nearly three-folds for MβG while V_max for soluble and MβG was 0.515 mM/min and 0.495 mM/min, respectively. Furthermore, MβG showed greater resistance to product inhibition mediated by galactose as compared to it soluble counterpart and exhibited excellent catalytic activity even after its fourth successive reuse. The remarkable bioconversion rates of lactose from milk in batch reactors further revealed an attractive catalytic efficiency of β-galactosidase adsorbed on surface functionalized AgNPs thereby promoting its use in the production of lactose free dairy products.     

Tubewell water quality and predictors of contamination in three flood-prone areas in Bangladesh

Aims: To measure enteric bacterial contamination of tubewells in three flood prone areas in Bangladesh and the relationship of bacteriological contamination with tubewell sanitary inspection scores. Methods and Results: Microbiologists selected 207 tubewells in three flood prone districts, assessed physical characteristics of the tubewells and collected a single water sample from each tubewell. Tubewell water samples were contaminated with total coliforms (41%, n = 85), thermotolerant coliforms (29%, n = 60) and Escherichia coli (13%, n = 27). Among contaminated wells, the median CFU of contamination per 100 ml was 8 (interquartile range, 2–30) total coliforms, 5 (interquartile range, 2–23) thermotolerant coliforms and 6 (interquartile range, 1–30) E. coli. There was no significant association between tubewell contamination with E. coli, thermotolerant coliforms or total coliforms and a poor sanitary inspection score, though a history of inundation was associated with contamination with both E. coli and thermotolerant coliforms. Conclusions: Tubewells in flood-prone regions of Bangladesh were commonly contaminated with low levels of faecal organisms, contamination that could not be predicted by examining the tubewell’s external characteristics. Significance and Impact of the Study: The forms currently used for sanitary inspection do not identify the most important causes of drinking water contamination in these communities.     

Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine‐tune hypoxic mitophagy

Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate mitophagy in response to stresses, or how mitophagy receptors sense stress signals to activate mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia‐induced mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia‐induced mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward mitophagy‐inducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine‐tune mitochondrial quality.     

Evaluation of biocompatibility and mechanical behavior of polyurethane elastomers based on chitin/1,4-butane diol blends

Chitin based polyurethane elastomers with potential as biomedical implants with tunable mechanical properties were synthesized by step growth polymerization techniques using poly(epsilon-caprolactone) (PCL) and 4,4'-diphenylmethane diisocyanate (MDI). The prepolymer was extended with different mass ratios of chitin and 1,4-butane diol (BDO). Molecular characterization was done using FTIR, 1H NMR and 13C NMR techniques. The mechanical properties of these polymers were improved with increase in the chitin contents. Optimum mechanical properties were obtained from elastomers extended with chitin in comparison to elastomers extended with BDO. Cytotoxicity of the synthesized polyurethane samples was affected by varying the chitin contents in the chemical composition of the final polyurethane (PU). It is revealed that the final polymers extended with chitin are preferred candidates for surgical threads with on going investigations into their in vitro biocompatibility and non-toxicity.