Mechanisms behind Temsirolimus Resistance Causing Reactivated Growth and Invasive Behavior of Bladder Cancer Cells In Vitro.

Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance.

Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental-par) RT112 and UMUC3 bladder cancer cells.

HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells.

Introduction: Although the mechanistic target of rapamycin (mTOR) might be a promising molecular target to treat advanced bladder cancer, resistance develops under chronic exposure to an mTOR inhibitor (everolimus, temsirolimus). Based on earlier studies, we proposed that histone deacetylase (HDAC) blockade might circumvent resistance and investigated whether HDAC inhibition has an impact on growth of bladder cancer cells with acquired resistance towards temsirolimus.

Results: The HDAC inhibitor valproic acid (VPA) significantly inhibited growth, proliferation and caused G0/G1 phase arrest in RT112 and UMUC-3.

Effects of dietary supplementation of organic acids and phytase on performance and intestinal histomorphology of broilers.

The present experiment was conducted to evaluate the effects of organic acids and phytase enzyme supplementation on performance and intestinal histomorphology of broilers. The experiment was done in a factorial arrangement 2 × 2 × 2 based on completely randomized design with eight treatments, five replicates with 12 chicks in each until 42 days of age. Diets included natural vinegar (0 and 2%), citric acid (CA; 0.

Growth and antioxidant status of broilers fed supplemental lysine and pyridoxine under high ambient temperature.

Three levels of lysine (90, 100 and 110% of Ross requirement) and of pyridoxine (3, 6 and 9 mg kg(-1)) were used in a 3 × 3 factorial experiment to investigate the growth and blood antioxidant ability of broilers under high ambient temperature. None of the dietary supplements affected the weight gain during the starter and grower periods. Although no significant differences were detected between the treatments during the entire period, high lysine level fed birds had a lower weight gain.

The in vitro antimicrobial activity of wound and skin cleansers at nontoxic concentrations.

Objective: To determine in vitro antibacterial activity of commercially available skin, wound, and skin/wound cleansers at cell-safe (nontoxic) concentrations.

Design: Saline and 19 other commercial wound and skin cleansers were evaluated for cytotoxic effects on mouse dermal fibroblasts. Cells were exposed to serial 10-fold dilutions of each cleanser until treatment-induced cytotoxicity was comparable to the baseline cytotoxicity of unexposed control fibroblasts.

Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity.

The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group.

NeutroPhase(®) in chronic non-healing wounds.

Chronic non-healing wounds, such as venous stasis ulcers, diabetic ulcers, and pressure ulcers are serious unmet medical needs that affect a patient's morbidity and mortality. Common pathogens observed in chronic non-healing wounds are Staphylococcus including MRSA, Pseudomonas, Enterobacter, Stenotrophomonas, and Serratia spp. Topical and systemically administered antibiotics do not adequately decrease the level of bacteria or the associated biofilm in chronic granulating wounds and the use of sub-lethal concentrations of antibiotics can lead to resistant phenotypes.

NVC-422 inactivates Staphylococcus aureus toxins.

Bacterial pathogens have specific virulence factors (e.g., toxins) that contribute significantly to the virulence and infectivity of microorganisms within the human hosts.

Virucidal mechanism of action of NVC-422, a novel antimicrobial drug for the treatment of adenoviral conjunctivitis.

Human adenoviral conjunctivitis is a highly contagious eye infection affecting millions of people world-wide. If untreated, it can further develop into keratitis, corneal ulceration, scarring and possible blindness. Despite the significant patient morbidity and socio-economic costs, it is an unmet medical need with no FDA approved treatment.

Structure stability/activity relationships of sulfone stabilized N,N-dichloroamines.

Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group.

Novel 3-chlorooxazolidin-2-ones as antimicrobial agents.

Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one 1a (X=H) as antibacterial and antifungal agents. The key findings were that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions.

Novel N-chloroheterocyclic antimicrobials.

Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic resistance are urgently needed. Toward this end, we prepared and investigated a novel series of N-chloroheterocycles. Of the compounds examined, the N-chloroamine series were found superior over N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability.

Chemical characterization and biological properties of NVC-422, a novel, stable N-chlorotaurine analog.

During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent, N-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce N,N-dichlorotaurine (NNDCT).

Stieglitz rearrangement of N,N-dichloro-beta,beta-disubstituted taurines under mild aqueous conditions.

New topical anti-infectives comprised of N,N-dichloro-beta,beta-disubstituted taurines [Tetrahedron Lett.2008, 49, 2193; Biorg. Med.

Hypochlorous Acid as a Potential Wound Care Agent: Part II. Stabilized Hypochlorous Acid: Its Role in Decreasing Tissue Bacterial Bioburden and Overcoming the Inhibition of Infection on Wound Healing.

Background: A topical antimicrobial that can decrease the bacterial bioburden of chronic wounds without impairing the wound's ability to heal is a therapeutic imperative. A stabilized form of hypochlorous acid (NVC-101) has been demonstrated in vitro and in standard toxicity testing to possess properties that could fulfill these criteria. Materials and Methods: Using a standard rodent model of a chronically infected granulating wound, various preparations of NVC-101 and multiple treatment regimens were investigated to evaluate the role of NVC-101 in decreasing tissue bacterial bioburden and overcoming the inhibition of infection on wound healing.