Understanding DNA Damage Response and DNA Repair in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.

Thermal micropolar and couple stresses effects on peristaltic flow of biviscosity nanofluid through a porous medium.

The main aim of the current study is to analyze couple stresses effects on MHD peristaltic transport of a micropolar non-Newtonian nanofluid. The fluid flows through a porous media between two horizontal co-axial tubes. The effects of radiation, chemical reaction, viscous and ohmic dissipation are considered. The inner tube is solid and uniform, while the outer tube has a sinusoidal wave traveling down its wall. The governing equations have been simplified using low-Reynolds number and long wave-length approximations, thus a semi-analytical solutions have been obtained using the homotopy perturbation method. Numerical results for the behaviors of the axial velocity, microrotation velocity, temperature and nanoparticles concentration with the physical parameters are depicted graphically through a set of graphs. Furthermore, the values of the skin friction coefficient, Nusselt and nano Sherwood numbers are computed and presented graphically through some draws. Moreover, the trapping phenomenon is discussed throughout a set of figures. The present study is very important in many medical applications, as the gastric juice motion in the small intestine when an endoscope is inserted through it. Further, gold nanoparticles are utilized in the remedy of cancer tumor.

Synthesis of aromatic lactone analogues of Lipoxin A4.

OBJECTIVE: Synthesis of novel aromatic Lipoxin A4 lactone analogues. RESULTS: Novel para-substituted aromatic lactone analogues of Lipoxin A4 have been synthesized in a convergent manner with six steps in the longest linear sequence in 12-13% yields, employing 2-deoxy-D-ribose as a chiral pool starting material and the classical E-selective Wittig olefination.

Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) are an emerging cause of bacterial antibiotic resistance by hydrolysing all classes of ß-lactams except monobactams, and the MBLs are not inhibited by clinically available serine-ß-lactamase inhibitors. Two of the most commonly encountered MBLs in clinical isolates worldwide - the New Delhi metallo-ß-lactamase (NDM-1) and the Verona integron-encoded metallo-ß-lactamase (VIM-2) - are included in this study. A series of several NH-1,2,3-triazoles was prepared by a three-step protocol utilizing Banert cascade reaction as the key step. The inhibitor properties were evaluated in biochemical assays against the MBLs VIM-2, NDM-1 and GIM-1, and VIM-2 showed IC50 values down to nanomolar range. High-resolution crystal structures of four inhibitors in complex with VIM-2 revealed hydrogen bonds from the triazole inhibitors to Arg228 and to the backbone of Ala231 or Asn233, along with hydrophobic interactions to Trp87, Phe61 and Tyr67. The inhibitors show reduced MIC in synergy assays with Pseudomonas aeruginosa and Escherichia coli strains harbouring VIM enzymes. The obtained results will be useful for further structural guided design of MBL inhibitors.

Carbonylative Suzuki-Miyaura couplings of sterically hindered aryl halides: synthesis of 2-aroylbenzoate derivatives.

We have developed a carbonylative approach to the synthesis of diversely substituted 2-aroylbenzoate esters featuring a new protocol for the carbonylative coupling of aryl bromides with boronic acids and a new strategy to favour carbonylative over non-carbonylative reactions. Two different synthetic pathways - (i) the alkoxycarbonylation of 2-bromo benzophenones and (ii) the carbonylative Suzuki-Miyaura coupling of 2-bromobenzoate esters - were evaluated. The latter approach provided a broader substrate tolerance, and thus was the preferred pathway. We observed that 2-substituted aryl bromides were challenging substrates for carbonylative chemistry favouring the non-carbonylative pathway. However, we found that carbonylative Suzuki-Miyaura couplings can be improved by slow addition of the boronic acid, suppressing the unwanted direct Suzuki coupling and, thus increasing the yield of the carbonylative reaction.

Interactive association between processing induced molecular structure changes and nutrient delivery on a molecular basis, revealed by cutting-edge vibrational biomolecular spectroscopy.

BACKGROUND: This study was conducted to determine protein molecular structure profiles and quantify the relationship between protein structural features and protein metabolism and bioavailability of blend pelleted products (BPP) based on co-products (canola or carinata) from processing with different proportions of pulse pea screenings and lignosulfonate chemical compound. METHOD: The protein molecular structures were determined using the non-invasive advanced vibrational molecular spectroscopy (ATR-FT/IR) in terms of chemical structure and biofunctional groups of amides (I and II), α-helix and ß-sheet. RESULTS: The results showed that increasing the level of the co-products in BPP significantly increased the spectral intensity of the amide area and amide height. The products exhibited similar protein secondary α-helix to ß-sheet ratio. The protein molecular structure profiles (amides I and II, α-helix to ß-sheet) were highly associated with protein degradation kinetics and intestinal digestion. In conclusion, the non-invasive vibrational molecular spectroscopy (ATR-FT/IR) could be used to detect inherent structural make-up characteristics in BPP. CONCLUSION: The molecular structural features related to protein biopolymer were highly associated with protein utilization and metabolism.

Connection of inherent structure with nutrient profiles and bioavailability of different co-products and by-products after processing using advanced grading and vibrational molecular spectroscopy.

This study aims to reveal connection and implication of molecular structure with nutrient profiles, utilization and bioavailability of both conventional and new co-products from bio-energy and bio-oil processing using grading and vibrational molecular spectroscopy with chemometics including univariate and multivariate techniques. The study focused on strategies to improve the utilization of the conventional and new co-products through chemical and heat processing treatments as well as the relationship of the molecular structural changes to nutrient bioavailability. The updated methods advanced molecular spectroscopy techniques with grading NIR, Globar FTIR, ATR-FTIR and Synchrotron SRFTIRM to study feed molecular structures were reviewed. This study provides an insight and a new approach on how to use grading and vibrational molecular spectroscopy to study molecular chemistry and molecular structure and molecular nutrition interaction.

A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design.

ß-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of ß-lactam resistance. The most prevalent resistance mechanism to ß-lactam antibiotics is expression of ß-lactamase enzymes. One way to overcome resistance caused by ß-lactamases, is the development of ß-lactamase inhibitors and today several ß-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R1 or R2 binders by their overall binding conformation in relation to the binding of the R1 and R2 side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC50 = 2.9 µM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.