Cancer

In recent decades, developments in glycobiology have enabled the use of glycopeptides as tools for studying complex diseases such as cancer. Mucin 1 (MUC1) is a heavily glycosylated transmembrane protein, altered in both expression and glycosylation pattern in human carcinomas of the epithelium. The presence of incomplete or truncated glycan structures, often capped by sialic acid, commonly known as tumor-associated carbohydrate antigens (TACAs), on the cell surface is a well-known cancer biomarker and therapeutic target for different types of cancer. Accumulating evidence suggests that TACAs are recognized by the endogenous carbohydrate binding proteins (lectins). These interactions frequently result in the development of a protumor microenvironment, favoring tumor initiation, progression, metastasis, and immune evasion. Macrophage galactose binding lectin (MGL) is a C-type lectin receptor found on antigen-presenting cells (APCs) which facilitates the uptake of carbohydrate antigens for antigen presentation, modulating the immune response in homeostasis, autoimmunity, and cancer. Considering the crucial role of tumor-associated forms of MUC1 and MGL in tumor immunology, a thorough understanding of this interaction is essential for it to be exploited for cancer vaccine strategies. The specific goal of this research is to synthesize structurally well-defined chemical probes, mono and multiple glycosylated MUC1 glycopeptide models bearing the Tn or sTn antigens, that provide control over the complexity of the chemical space of multivalent ligands. For this purpose, a concise scheme was developed for the large-scale synthesis of the Tn and sTn antigen building blocks in a relatively high yield with moderate stereoselectivity. Thiophenyl glycoside donors, in the presence TfOH/NIS or TMSOTf/NIS as promoter systems, were used for the galactosylation and sialylation steps of the amino acid building block synthesis, respectively. We explored the effect of the activator, temperature, solvent, and excess equivalent of sialic acid thioglycoside donor on the sialylation reaction.

Cancer is a leading cause of death in the U.S and across the world, with estimates indicating 17 million new cancer cases in 2018, 9.5 million of which resulted in death. Statistics show that in the past 20 years cancer death rates have decreased 27% due to emerging therapies. The use of chemotherapies to kill fast-growing cells in the body has become one of the most common cancer treatments in the world today. Chemotherapy-Induced Peripheral Neuropathies (CIPNs) are the most common side effects caused by chemotherapeutic agents. CIPNs have a prevalence of up to 85% in cancer patients undergoing chemotherapy. CIPNs triggered by chemotherapeutic drug use severely damage nerves branching from either the brain or spinal cord, initiating the development of acute and/or chronic symptoms. Platinum-based and taxane-based chemotherapeutics are among the most potent and versatile drugs available for combating cancer. The two of these drugs, carboplatin and docetaxel, are known to cause peripheral neuropathies and central neurotoxicity and were the focus of this project.

Dose uniformity in the Planning Target Volume (PTV) can induce a higher-than-expected dose distribution in the nearby critical organs. The goal of this study is to evaluate the influence of the Planning Target volume dose uniformity on the surrounding critical organs (OAR).
Ten cases of anonymized patients’ data were selected for our study including: Breast cancer, Brain cancer, Head and Neck cancer, Lung and Prostate calculations of Conformity indices, Biological Effective Doses (BED), Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) were used to calculate the dose distribution in PTV as well as the dose delivered to the surrounding critical organs of each PTV. We assume that the tumors PTVs have homogeneous density as well as the surrounding normal tissue.
Conformity indices (CI) for Breast (PTV) are between 1.8 – 1.9, for Brain (PTV) are between 1.6 – 2.0, for Lungs are 1.5 – 1.6, for Prostate are between 0.4 – 0.5, for Head and Neck are 0.3 – 0.4. Dose uniformity in all the PTVs is 1.089 which is a good indication of the quality of treatment delivered to the tumor. TCP is averaging of value of 87.94 and NTCP is 3.4445.

Epigenetic dysregulation has been implicated in oncogenesis, with post-translational histone modifications being linked to cancer progression. WSTF/BAZ1B forms chromatin-remodeling complexes with other proteins and lowers cancer survival outcomes. Treatment resistance causes >90 % of all cancer deaths. In particular, cancers develop tolerance to cisplatin-induced genotoxicity. It is hypothesized that the BAZ1B bromodomain, PHD finger, and DDT domain recognize epigenetic modifications, contributing to cisplatin resistance in cancers. To test this, the domains were expressed in Rosetta 2 BL21(DE3) and Rosetta 2 BL21(DE3) PLysS Escherichia coli strains. Soluble proteins were extracted, purified, and then analyzed using pulldown assays and modified histone peptide arrays. The DDT and PHD finger domains were found to bind to specific histone modifications with the DDT domain also displayed DNA-binding properties. Some of the identified histone modifications have known roles/correlations in normal and cancer cells, implicating BAZ1B as an agent in oncogenesis, treatment resistance, and as a therapeutic target.

The lack of physiologically relevant human esophageal cancer models has as a result that many esophageal cancer studies are encountering major bottleneck challenges in achieving breakthrough progress. To address the issue, here a 3D esophageal tumor tissue model was engineered using a biomimetic decellularized esophageal matrix in a customized bioreactor. To obtain a biomimetic esophageal matrix, a detergent-free, rapid decellularization method was developed to decellularize porcine esophagus. The decellularized esophageal matrix (DEM) was characterized and the DEM was utilized for the growth of esophageal cancer cell KYSE30 in well plates and the bioreactor. Then the expression of cancerrelated markers of KYSE30 cells was analyzed and compared with formalin-fixed, paraffin-embedded (FFPE) esophageal squamous cell carcinoma (ESCC) tissue biospecimens. Results show that the detergent-free decellularization method preserved the esophageal matrix components and effectively removed cell nucleus. KYSE30 cancer cells proliferated well on and inside the DEM. KYSE30 cells cultured on the DEM in the dynamic bioreactor show different cancer marker expressions than those in the static well plate, and also share some similarities to the FFPE-ESCC biospecimens.

Serine/Arginine splicing factor 1 (SRSF1), a member of the Serine/Arginine rich (SR) RNA-binding proteins (RBPs) family, regulates mRNA biogenesis at multiple steps and is deregulated in cancer and autoimmune diseases. Preliminary studies show that members of the SR protein family play a role in cellular transcription. We investigated SRSF1’s role in cellular gene transcription utilizing time-course RNA-Seq and nuclear run-on assays, validating a subset of genes transcriptionally regulated following SRSF1 overexpression. Pathway analysis showed that genes in the TNF/IL17 pathways were enriched in this dataset. Furthermore, we showed that MyD88, a strong activator of TNF transcription through transcription factors NF-κB and AP-1, is a primary target of SRSF1’s transcriptional activity. We propose that SRSF1 activates the transcription factors NF-κB and AP-1 through MyD88 pathway. SRSF1 overexpression regulates several genes that are deregulated in malignancies and immune disease, suggesting a role for SRSF1’s transcriptional activity in oncogenesis and immune response regulation.

Prostate cancer is one of the leading causes of death in men aged 40-55. Genistein isoflavone (4', 5', 7-trihydroxyisoflavone) is a dietary phytochemical with demonstrated anti-tumor activities in a variety of cancers. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy drug, primarily used for secondary treatment of ovarian,cervical and small cell lung cancers. This study was to demonstrate the potential anticancer activities and synergy of topotecan-genistein combination in LNCaP prostate cancer cells. The potential efficacy and mechanism of topotecan/genistein-induced cell death was investigated... Results: The overall data indicated that i) both genistein and topotecan induce cellular death in LNCaP cells, ii) topotecan-genistein combination was significantly more efficacious in reducing LNCaP cell viabiligy compared to either genistein or topotecan alone, iii) in all cases, cell death was primarily through apoptosis, via the activation of the intrinsic pathway, iv) ROS levels were increased and VEGF expression was diminished significantly with the topotecan-genistein combination treatment, v) genetic analysis of topotecan-genistein treatment groups showed changes in genetic expression levels in pathway specific apoptotic genes.... Conclusion: Treatments involving topotecan-genistein combination may prove to be an attractive alternative phytotherapy of adjuvant therapy for prostate cancer.

Cancer is a large group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled or checked, it results in death. Cancer is one of the leading causes of death in Western societies. In the United States, cancer is the second leading killer. However, many cancers can be cured if detected early and treated promptly. This paper analyzes the synthesis of thiadiazole- and diazepine-based acyclonucleosides with potential anticancer or antiviral activity.

The purpose of this research is to compare the surface dose outside the treatment area for different breast cancer irradiation modalities using Thermoluminescence Dosimeters (TLDs). Five different modalities are included in this study: Accuboost, Photon boost, Electron boost, Strut-Adjusted Volume Implant (SAVI), and Mammosite Multi-lumen (ML).Six points of interest (POI) on the breast cancer patients had been selected for the TLDs placement. Data from 25 breast cancer patients at Lynn Cancer Institute of the Boca Raton Regional Hospital were included in the study. The measured percentage ranges of the averaged doses at the six POIs for the different modalities are: Sternum 0.26% - 3.26%, Shoulder 0.33% - 2.79%, Eye 0.26% - 1.32%, Thyroid 0.20% - 2.75%, CLB 0.2% - 5.46%, Lower Abdomen 0.16% - 2.25%.

We attempted to understand the molecular regulators that impact inflammation using a rat model of human sensation-seeking/risk-taking trait for drug and stress vulnerability, based on their exploratory behavior displaying high rates (HRs) or low rates of locomotor reactivity (LRs) to environmental stress. We found that HRs have a pro-inflammatory phenotype as indicated by increased protein expression of the inflammatory cytokine TNF-(Sa(B. Furthermore, we found that HRs have a lower gene expression of the glucocorticoid receptor and histone deacetylase 2 which are known to play an immunosuppressive role. Autophagy (macroautophagy) is a homeostatic process needed for cell maintenance, growth and proliferation and known to assist in tumor survival. FYVE and coiled-coil domain containing 1 (FYCO1) is a novel protein implicated to assist in the plus-end directed trafficking and fusion of autophagosomes. In these studies, we show that FYCO1 gene expression among human breast cell lines of varying degrees of malignancy.