Novel colchicine derivative CR42-24 demonstrates potent anti-tumor activity in urothelial carcinoma.

Bladder cancers, and specifically urothelial carcinoma, have few effective treatment options, and tumors typically develop resistance against standard of care chemotherapies leading to significant mortality. The development of alternative therapies with increased selectivity and improved tolerability would significantly impact this patient population. Here, we investigate a novel colchicine derivative, CR42-24, with increased selectivity for the ßIII tubulin subtype as a treatment for urothelial carcinoma. ßIII tubulin is a promising target due to its low expression in healthy tissues and its clinical association with poor prognosis. This study demonstrated that CR42-24 is selectively cytotoxic to several cancer cell lines at low nanomolar IC50, with high activity in bladder cancer cell lines both in vitro and in vivo. CR42-24 monotherapy in an aggressive urothelial carcinoma xenograft model results in effective control when treated early. We observed significant ablation of large tumors and patient-derived xenografts at low doses with excellent tolerability. CR42-24 was highly synergistic in combination with the standard of care chemotherapies gemcitabine and cisplatin, further increasing its therapeutic potential as a novel treatment for urothelial carcinoma.

Disassembly of microtubules by intense terahertz pulses.

The biological effects of terahertz (THz) radiation have been observed across multiple levels of biological organization, however the sub-cellular mechanisms underlying the phenotypic changes remain to be elucidated. Filamentous protein complexes such as microtubules are essential cytoskeletal structures that regulate diverse biological functions, and these may be an important target for THz interactions underlying THz-induced effects observed at the cellular or tissue level. Here, we show disassembly of microtubules within minutes of exposure to extended trains of intense, picosecond-duration THz pulses. Further, the rate of disassembly depends on THz intensity and spectral content. As inhibition of microtubule dynamics is a mechanism of clinically-utilized anti-cancer agents, disruption of microtubule networks may indicate a potential therapeutic mechanism of intense THz pulses.

Water only fasting and its effect on chemotherapy administration in gynecologic malignancies.

OBJECTIVE: As a protective response, during starvation organisms withdraw energy from growth and reproduction to focus on cellular maintenance. Cancer cells cannot undergo this differential response which has been theorized as an adjunct to improve both the effect of chemotherapy treatment and reduce treatment side effects. We sought to investigate the feasibility and effect of short-term fasting in patients receiving chemotherapy for gynecologic malignancy. METHODS: A randomized control trial was conducted of women with gynecologic malignancies receiving at least 6 planned chemotherapy cycles. Fasting patients maintaining a water-only fast for 24 h before and 24 h following each chemotherapy cycle were compared to nonfasting patients. Treatment related side effects and quality of life (QOL) was assessed using NCCN-FACT FOSI-18 questionnaire. RESULTS: Analysis included data from 120 cycles of chemotherapy. The majority of patients had stage 3 and 4 malignancy requiring multi-agent chemotherapy. Eleven patients had ovarian, 8 had uterine, and 1 had cervical cancer. Ninety percent received taxane and platinum-based doublet therapy. Weight loss and unanticipated hospitalizations were similar between treatment groups. Fewer dose reductions or delays were seen in the fasting group. There was no significant difference in mean QOL scores, but fasting group QOL scores improved over the course of treatment to a level that reached the minimal clinically important difference. CONCLUSION: A 48-h fast is well tolerated without increasing weight loss, hospital admissions, or chemotherapy dose reduction/delays. Fasting resulted in fewer treatment modifications and improved quality of life scores over the course of treatment.

Economic disparities in Appalachia linked to risk factors for long-term health for estrogen positive breast cancer patients.

BACKGROUND: Breast cancer is the second leading cause of cancer death for women in the United States and mortality from cancer is more common among individuals in the Appalachian region compared to the rest of the country. We examined how risk factors for long-term health outcomes for Estrogen positive breast cancer patients differed by county economic status in southern Appalachia. METHODS: Data was collected through retrospective data mining of patient medical files (N = 238). Using the self-reported zipcode, patients were classified into county economic status. At-risk and distressed designations were also rural counties. Bi-variate statistical analyses were used to evaluate how demographic, behavioral, health risk factors differed across economic statuses. RESULTS: For demographic factors, fewer single individuals lived in at-risk counties and older individuals lived in distressed counties. For health behaviors, more individuals in transitional counties report drinking alcohol but more individuals in distressed counties reported adhering to medication. For morbidity, more individuals in distressed counties reported having diabetes or a circulatory disease. CONCLUSIONS: Many risk factors differed across county economic statuses. Therefore, doctors must consider the patient's context as a risk factor not just their individual characteristics. Patients from economically distressed counties may be at higher risk for treatment complications due to a larger proportion of co-morbidities and older age. Because many risk factors (eg, previous cancer, BMI) are similarly proportioned across Appalachian economic statuses, ER+ breast cancer patients in Appalachia may be at a similarly high risk for health complications compared to the rest of the country.

Response to Alternating Electric Fields of Tubulin Dimers and Microtubule Ensembles in Electrolytic Solutions.

Microtubules (MTs), which are cylindrical protein filaments that play crucial roles in eukaryotic cell functions, have been implicated in electrical signalling as biological nanowires. We report on the small-signal AC ("alternating current") conductance of electrolytic solutions containing MTs and tubulin dimers, using a microelectrode system. We find that MTs (212 nM tubulin) in a 20-fold diluted BRB80 electrolyte increase solution conductance by 23% at 100 kHz, and this effect is directly proportional to the concentration of MTs in solution. The frequency response of MT-containing electrolytes exhibits a concentration-independent peak in the conductance spectrum at 111 kHz (503 kHz FWHM that decreases linearly with MT concentration), which appears to be an intrinsic property of MT ensembles in aqueous environments. Conversely, tubulin dimers (42 nM) decrease solution conductance by 5% at 100 kHz under similar conditions. We attribute these effects primarily to changes in the mobility of ionic species due to counter-ion condensation effects, and changes in the solvent structure and solvation dynamics. These results provide insight into MTs' ability to modulate the conductance of aqueous electrolytes, which in turn, has significant implications for biological information processing, especially in neurons, and for intracellular electrical communication in general.