A Novel Class of Human ADAM8 Inhibitory Antibodies for Treatment of Triple-Negative Breast Cancer.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach.

The Fitness of Beta-Lactamase Mutants Depends Nonlinearly on Resistance Level at Sublethal Antibiotic Concentrations.

Adaptive evolutionary processes are constrained by the availability of mutations which cause a fitness benefit and together make up the fitness landscape, which maps genotype space onto fitness under specified conditions. Experimentally derived fitness landscapes have demonstrated a predictability to evolution by identifying limited "mutational routes" that evolution by natural selection may take between low and high-fitness genotypes. However, such studies often utilize indirect measures to determine fitness.

Comparison of postoperative analgesia with two different doses of dexmedetomidine as an adjuvant to ropivacaine in adductor canal block for unilateral total knee replacement surgery: A randomized double-blinded study.

Background And Aims: Multimodal analgesia is used to treat severe postoperative pain (POP) in total knee replacement (TKR) surgery. Adjuvants are used with local anesthetics to improve the quality and duration of pain relief. Studies comparing different doses of dexmedetomidine in adductor canal block (ACB) are sparse to date.

Unpredictable repeatability in molecular evolution.

The extent of parallel evolution at the genotypic level is quantitatively linked to the distribution of beneficial fitness effects (DBFE) of mutations. The standard view, based on light-tailed distributions (i.e.

Stochastic establishment of β-lactam-resistant mutants reveals conditions for collective resistance.

For antibiotic resistance to arise, new resistant mutants must establish in a bacterial population before they can spread via natural selection. Comprehending the stochastic factors that influence mutant establishment is crucial for a quantitative understanding of antibiotic resistance emergence. Here, we quantify the single-cell establishment probability of four strains expressing β-lactamase alleles with different activity against the antibiotic cefotaxime, as a function of antibiotic concentration in both unstructured (liquid) and structured (agar) environments.

Antibiotic Breakdown by Susceptible Bacteria Enhances the Establishment of β-Lactam Resistant Mutants.

For a better understanding of the evolution of antibiotic resistance, it is imperative to study the factors that determine the initial establishment of mutant resistance alleles. In addition to the antibiotic concentration, the establishment of resistance alleles may be affected by interactions with the surrounding susceptible cells from which they derive, for instance the release of nutrients or removal of the antibiotic. Here, we investigate the effects of social interactions with surrounding susceptible cells on the establishment of mutants with increasing β-lactamase activity (i.

Predictable properties of fitness landscapes induced by adaptational tradeoffs.

Fitness effects of mutations depend on environmental parameters. For example, mutations that increase fitness of bacteria at high antibiotic concentration often decrease fitness in the absence of antibiotic, exemplifying a tradeoff between adaptation to environmental extremes. We develop a mathematical model for fitness landscapes generated by such tradeoffs, based on experiments that determine the antibiotic dose-response curves of strains, and previous observations on antibiotic resistance mutations.

Universal lower bound on the free-energy cost of molecular measurements.

The living cell uses a variety of molecular receptors to read and process chemical signals that vary in space and time. We model the dynamics of such molecular level measurements as Markov processes in steady state, with a coupling between the receptor and the signal. We prove exactly that, when the signal dynamics is not perturbed by the receptors, the free energy consumed by the measurement process is lower bounded by a quantity proportional to the mutual information.

miR-720 is a downstream target of an ADAM8-induced ERK signaling cascade that promotes the migratory and invasive phenotype of triple-negative breast cancer cells.

Background: ADAM8 (a disintegrin and metalloproteinase 8) protein promotes the invasive and metastatic phenotype of triple-negative breast cancer (TNBC) cells. High ADAM8 expression in breast cancer patients is an independent predictor of poor prognosis. Here, we investigated whether ADAM8 regulates specific miRNAs, their roles in aggressive phenotype, and potential use as biomarkers of disease.

Intelligent Access to Sequence and Structure Databases (IASSD) - an interface for accessing information from major web databases.

Unlabelled: With the advent of age of big data and advances in high throughput technology accessing data has become one of the most important step in the entire knowledge discovery process. Most users are not able to decipher the query result that is obtained when non specific keywords or a combination of keywords are used. Intelligent access to sequence and structure databases (IASSD) is a desktop application for windows operating system.

Numerical test of hydrodynamic fluctuation theory in the Fermi-Pasta-Ulam chain.

Recent work has developed a nonlinear hydrodynamic fluctuation theory for a chain of coupled anharmonic oscillators governing the conserved fields, namely, stretch, momentum, and energy. The linear theory yields two propagating sound modes and one diffusing heat mode, all three with diffusive broadening. In contrast, the nonlinear theory predicts that, at long times, the sound mode correlations satisfy Kardar-Parisi-Zhang scaling, while the heat mode correlations have Lévy-walk scaling.

Overexpression of Mcl-1 confers multidrug resistance, whereas topoisomerase IIβ downregulation introduces mitoxantrone-specific drug resistance in acute myeloid leukemia.

Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia.

Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017): a novel scaffold that resensitizes multidrug resistant leukemia cells to chemotherapy.

Multidrug resistance (MDR) is a major hurdle in the treatment of cancer, and there is a pressing need for new therapies. We have recently developed ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017), derived from a dual inhibitor of Bcl-2 and SERCA proteins, sHA 14-1, with selective cytotoxicity toward MDR cancer cell lines in vitro. In this study, we present new evidence for its therapeutic potential in treatment of MDR cancers and offer mechanistic insights toward its preferential targeting of drug-resistant cancer.

Structure-activity relationship and molecular mechanisms of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and its analogues.

Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells.

Effect of hydrodynamic interaction on polymeric tethers.

Weak bonds are ubiquitous in biological structures. They often act as adhesive contacts within an extended structure, for example, the internal bonds in a folded protein or a DNA/RNA loop. They also act as linkers between two structures, for example, a protein grafted in a cell membrane or a protein linking the cell membranes of two neighboring cells.

A facile asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines.

A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines from a single starting material is described. Reductive cyclization of (S(S))-gamma-chloro-N-tert-butanesulfinyl ketimines with LiBHEt(3) in THF at -78 to 23 degrees C afforded (S(S),R)-N-tert-butanesulfinyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1). The diastereoselectivity is controlled effectively by the choice of reducing agent.

Structure-activity relationship and molecular mechanisms of ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4h-chromene-3-carboxylate (sha 14-1) and its analogues.

Rapid development of multiple drug resistance against current therapies is a major barrier in the treatment of cancer. Therefore, anticancer agents that can overcome acquired drug resistance in cancer cells are of great importance. Previously, we have demonstrated that ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate (5a, sHA 14-1), a stable analogue of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (6, HA 14-1), mitigates drug resistance and synergizes with a variety of cancer therapies in leukemia cells.

Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria.

HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog of HA 14-1 (sHA 14-1). The current study characterizes its mode of action.

sHA 14-1, a stable and ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human leukemia cell.

HA 14-1, a small-molecule antagonist against anti-apoptotic Bcl-2 proteins, was demonstrated to induce selective cytotoxicity toward malignant cells and to overcome drug resistance. Due to its poor stability and the reactive oxygen species (ROS) generated by its decomposition, chemical modification of HA 14-1 is needed for its future development. We have synthesized a stabilized analog of HA 14-1--sHA 14-1, which did not induce the formation of ROS.