The SAR analysis of dietary polyphenols and their antagonistic effects on bortezomib at physiological concentrations

Background: Bortezomib (BTZ), a primary treatment for MM, but its effectiveness can be reduced by interactions with vicinal diol moieties (VDMs) in polyphenols. Despite this, it’s debated whether BTZ therapy necessitates avoiding polyphenol-rich products, given the low bioavailability of polyphenols. Additionally, it remains unclear whether the structure of polyphenols contributes to their BTZ antagonism. Therefore, our study aims to unravel the structure-activity relationship of dietary polyphenols and their BTZ antagonism at daily diet-achievable physiological concentrations.Methods: We assessed the antagonistic effects of 25 polyphenols against BTZ using cell viability assays in RPMI 8226 cells. ChemGPS-NP helped analyze the structural similarity. Additionally, long-term cytotoxicity assays evaluated these effects at physiologically relevant concentrations.Results: By cell viability assays, we found a positive correlation between the number of VDMs in gallotannins and their BTZ antagonism. Moreover, the origin and configuration of VDMs, rather than the total VDM concentration, play a pivotal role in the combined antagonistic effects against BTZ in gallotannins. Additionally, ChemGPS-NP analysis indicated that the aromaticity and C-3 hydroxyl group in flavonoids’ C-rings enhance their BTZ antagonism. Finally, long-term cytotoxicity assays reveal that gallic acid (GA), epigallocatechin (EGC), and epigallocatechin gallate (EGCG), at their physiological concentrations—attainable through tea consumption—significantly and synergistically antagonize BTZ.Conclusion: Due to the potential for these polyphenols to reduce the effectiveness of BTZ, it is advisable for MM patients undergoing BTZ treatment to reduce their consumption of foods high in VDM-containing polyphenols

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable

Doctoral Recitals

Recital presented at the UNT College of Music Voertman Hall in partial fulfillment of the Doctor of Musical Arts (DMA) degree

Doctoral Recitals

Recital presented at the UNT College of Music Recital Hall in partial fulfillment of the Doctor of Musical Arts (DMA) degree

Doctoral Recitals

Recital presented at the UNT College of Music Voertman Hall in partial fulfillment of the Doctor of Musical Arts (DMA) degree

Doctoral Recitals

Recital presented at the UNT College of Music Voertman Hall in partial fulfillment of the Doctor of Musical Arts (DMA) degree

Evaluation of the harmonic scalpel in breast conserving and axillary staging surgery

Background: The ultrasonically activated scalpel has been introduced as an alternative to conventional methods of hemostasis in surgical procedures. The present study investigated the benefits of using the Harmonic FOCUS (HF) scalpel in breast-conserving surgery (BCS) and in axillary staging surgery. Methods: All early-stage breast cancer patients who underwent BCS and axillary staging surgery between January 2009 and December 2010 were retrospectively identified. Those patients treated with the HF scalpel were defined as the HF group, while patients whose surgery involved the electrocautery and the clamp-and-tie technique were designated as the conventional method (CM) group. Both groups were subsequently divided into the axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) subgroups, respectively. Results: A total of 89 patients were included in the study, with 41 patients in the HF group and 48 in the CM group. There were 13 patients in the SLNB subgroup and 28 were in the ALND subgroup of the HF group, and 21 patients were in the SLNB subgroup and 27 in the ALND subgroup of the CM group. Multiple linear regression analysis revealed that the length of surgery was significantly reduced in the ALND subgroup of the HF group (β = -16.70, p < 0.001). The incidence of axillary numbness was significantly decreased in the ALND subgroup of the HF group, with the results measured by multiple logistic regression analysis (OR = 0.27, p = 0.044). No statistically significant differences were identified concerning intraoperative blood loss, postoperative drainage, and seroma between the HF and CM groups. Conclusion: Using the Harmonic FOCUS scalpel in breast conserving surgery and axillary lymph mode dissection significantly reduced the length of surgery and decreased the axillary numbness rate as compared to conventional methods