Increasing the Efficacy of Doxorubicin Against Breast Cancer

In the United States, breast cancer accounts for one in three cancer diagnoses in women, making it the most common type of cancer in women. One important chemotherapeutic agent used to treat breast cancer is doxorubicin, an anthracycline compound that causes cell death by damaging DNA in addition to producing reactive oxygen species. Previously, the Berdis lab developed an artificial nucleoside analog designated 5-NIdR that improves the efficacy of DNA damaging agents used against brain cancer. This nucleoside works by inhibiting the replication of damaged DNA created by certain chemotherapeutic agents. In this project, we tested the ability of 5-NIdR to increase the efficacy of doxorubicin in the treatment of breast cancer. This was accomplished by comparing the effects of doxorubicin in the absence and presence of 5-NIdR using MCF-7 breast cancer cells and non-cancerous fibroblasts as models. Our studies show that breast cancer cells are highly resistant to doxorubicin, displaying an LD50 value of 840 nM which is 8-fold higher than that measured against non-cancerous fibroblasts (LD50 = 105 nM). Combining 5-NIdR with doxorubicin kills more cells compared to treatment with either doxorubicin or 5-NIdR used alone.https://engagedscholarship.csuohio.edu/u_poster_2018/1027/thumbnail.jp

Mechanism of action by which 5-NIdR acts as a therapeutic agent against brain cancer

Approximately 10,000 people in the United States are diagnosed annually with a brain tumor. In addition, the prognosis for brain cancer patients is poor as these cancers have low survival rates of less than 10%. One important chemotherapeutic agent used to treat brain cancer is temozolomide, an alkylating agent that causes cell death by damaging DNA. In this project, we tested the ability of a specific non-natural nucleoside developed in our lab, designated 5-NIdR, to increase the efficacy of temozolomide against brain cancer. Animal studies using xenograft mice were performed to evaluate the in vivo efficacy of this drug combination against brain cancer. Results indicate that treatment with 5-NIdR does not affect the rate of tumor growth compared to treatment with vehicle control. While treatment with temozolomide slows the rate of tumor growth by 2-fold, more striking results are obtained when 5-NIdR is combined with temozolomide as this drug combination causes complete tumor regression within two weeks of treatment. To better define the cellular mechanism for this effect, a series of cell-based studies were performed to compare the cytotoxic effects of temozolomide alone and in combination with 5-NIdR. Flow cytometry experiments measuring Annexin V staining as a marker for apoptosis demonstrate that cells treated with 5-NIdR and temozolomide accumulate show significantly higher levels of apoptosis compared to cells treated with 5-NIdR or temozolomide alone. Experiments measuring cell-cycle progression demonstrate that treatment with 5-NIdR and temozolomide causes cancer cells to accumulate at S-phase before undergoing apoptosis. The block at S-phase likely results from the ability of 5-NIdR to inhibit the replication of damaged DNA created by temozolomide. Consistent with this mechanism, significantly higher levels of single- and double-strand DNA breaks are detected in cancer cells treated with 5-NIdR and temozolomide compared to cells treated individually with either agent. Collectively, these studies provide additional pharmacological evidence for combining 5-NIdR and temozolomide as a possible treatment strategy to effectively treat brain cancers.https://engagedscholarship.csuohio.edu/u_poster_2015/1019/thumbnail.jp

Pharmacological and Pre-Clinical Testing of 5-NIdR as a New Therapeutic Agent Against Brain Cancer

Approximately 4,000 children in the United States are diagnosed annually with a brain tumor. Brain cancers are the deadliest of all pediatric cancers as they have survival rates of less than 20%. Although surgery and radiation therapy are widely used to treat adult patients, chemotherapy is the primary therapeutic option for children. One important chemotherapeutic agent is temozolomide, an alkylating agent that causes cell death by damaging DNA. In this project, we tested the ability of a specific non-natural nucleoside developed in our lab, designated 5-NIdR, to increase the efficacy of temozolomide against brain cancer. Cell-based studies demonstrate that the combination of 5-NIdR and temozolomide kills more cells compared to treatment with either temozolomide or 5-NIdR used alone. Microscopy techniques demonstrate that the combination of 5-NIdR and temozolomide causes cell death via apoptosis rather than necrosis. Animal studies using xenograft (nude) mice were performed to evaluate the in vivo efficacy and safety of this drug combination against brain cancer. Preliminary results are provided which indicate that treatment with 5-NIdR does not inhibit the rate of tumor growth. In contrast, treatment with temozolomide reduces the rate of tumor growth but does not lead to the complete elimination of the tumor. Striking results are obtained using 5-NIdR and temozolomide together as this drug combination causes a significant reduction in tumor size. Finally, mice treated with the combination of 5-NIdR and temozolomide do not show overt signs of side effects such as weight loss, dehydration, or fatigue. Collectively, these studies provide pharmacological evidence for combining 5-NIdR and temozolomide as a new treatment strategy to effectively treat brain cancers.https://engagedscholarship.csuohio.edu/u_poster_2014/1018/thumbnail.jp

Total Reflection and Negative Refraction of Dipole-Exchange Spin Waves at Magnetic Interfaces: Micromagnetic Modeling Study

We demonstrated that dipole-exchange spin waves traveling in geometrically restricted magnetic thin films satisfy the same laws of reflection and refraction as light waves. Moreover, we found for the first time novel wave behaviors of dipole-exchange spin waves such as total reflection and negative refraction. The total reflection in laterally inhomogeneous thin films composed of two different magnetic materials is associated with the forbidden modes of refracted dipole-exchange spin waves. The negative refraction occurs at a 90 degree domain-wall magnetic interface that is introduced by a cubic magnetic anisotropy in the media, through the anisotropic dispersion of dipole-exchange spin waves.Comment: 13 pages, 5 figure

Inhibiting Translesion DNA Synthesis as an Approach to Combat Drug Resistance to DNA Damaging Agents

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using click chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anticancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine

Serum BDNF levels in patients with gambling disorder are associated with the severity of gambling disorder and Iowa Gambling Task indices

Background and aims Gambling disorder (GD) shares many similarities with substance use disorders (SUDs) in clinical, neurobiological, and neurocognitive features, including decision-making. We evaluated the relationships among, GD, decision-making, and brain-derived neurotrophic factor (BDNF), as measured by serum BDNF levels. Methods Twenty-one male patients with GD and 21 healthy sex- and age-matched control subjects were evaluated for associations between serum BDNF levels and the Problem Gambling Severity Index (PGSI), as well as between serum BDNF levels and Iowa Gambling Task (IGT) indices. Results The mean serum BDNF levels were significantly increased in patients with GD compared to healthy controls. A significant correlation between serum BDNF levels and PGSI scores was found when controlling for age, depression, and duration of GD. A significant negative correlation was obtained between serum BDNF levels and IGT improvement scores. Discussion These findings support the hypothesis that serum BDNF levels constitute a dual biomarker for the neuroendocrine changes and the severity of GD in patients. Serum BDNF level may serve as an indicator of poor decision-making performance and learning processes in GD and help to identify the common physiological underpinnings between GD and SUDs

Highly circularly polarized white light using a combination of white polymer light-emitting diode and wideband cholesteric liquid crystal reflector

We present a simple and intriguing device that generates highly circularly polarized white light. It comprises white polymer light-emitting diodes (WPLEDs) attached to a wideband cholesteric liquid crystal (CLC) reflector with a wide photonic bandgap (PBG) covering the visible range. The degree of circular polarization realized is very high over the visible range. The wide PBG was realized by introducing a gradient in pitch of the cholesteric helix by controlling the twisting power within the CLC medium. WPLEDs fabricated using a ternary (red, green, and blue) fluorescent polymer blend with the same moiety showed a low turn-on voltage, high brightness, high efficiency, and good color stability.open0

Myricetin: A Naturally Occurring Regulator of Metal-Induced Amyloid-β Aggregation and Neurotoxicity

No AbstractPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84385/1/1198_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/84385/2/cbic_201000790_sm_miscellaneous_information.pd