Risk Factors Associated with Pressure Ulcers among Home Health Care Patients; Riyadh, Saudi Arabia

Background: Patients, professionals, and health care systems are faced with a serious problem of pressure ulcers. They represent a significant occurrence and prevalence throughout the world. Their character iatrogenic states that its appearance is preventable, and its incidence is an indicator of scientific and technical quality both in primary care and specialized care. Surgery may be necessary to accelerate the healing process, although most pressure ulcers are usually treated with debridement and conservative therapy. Their reported incidence and prevalence are significant worldwide. Objectives: The study's objectives are to identify the pressure ulcer risk factors in patients getting home health care, as well as to look at the quantity, type, and characteristics of pressure ulcers as well as patient comorbidities. Methods: Cross-sectional study, Home Care Nursing personnel questionnaire to determine the Risk Factors of Pressure Ulcers, patient comorbidities, and the number, and characteristics of pressure ulcers among patients receiving home care in Riyadh, Saudi Arabia. Results: PU is prevalent among the studied participants in Saudi Arabia, about 55% of these ulcers showed noticeable distraction of skin and/or deeper soft tissue against a bony prominence. We have also found a significant relationship between PU and gender, diabetes mellitus, hypertension, incontinence issues, nutritional status, and physical status, cerebrovascular accidents, trauma, and chronic kidney disease. Conclusion: Different risk factors are associated with PU such as diabetes mellitus, hypertension, and nutritional, and physical status. To monitor and promote best practices in skin care for highly dependent patients, continued measurement and evaluation of PU incidence, it is recommended more research of risk factors of PU development be assessed at home Health care Centers

The effect of Link N on differentiation of human bone marrow-derived mesenchymal stem cells

INTRODUCTION: We previously showed that Link N can stimulate extracellular matrix biosynthesis by intervertebral disc (IVD) cells, both in vitro and in vivo, and is therefore a potential stimulator of IVD repair. The purpose of the present study was to determine how Link N may influence human mesenchymal stem cell (MSC) differentiation, as a prelude to using Link N and MSC supplementation in unison for optimal repair of the degenerated disc. METHODS: MSCs isolated from the bone marrow of three osteoarthritis patients were cultured in chondrogenic or osteogenic differentiation medium without or with Link N for 21 days. Chondrogenic differentiation was monitored by proteoglycan staining and quantitation by using Alcian blue, and osteogenic differentiation was monitored by mineral staining and quantitation by using Alzarin red S. In addition, proteoglycan secretion was monitored with the sulfated glycosaminoglycan (GAG) content of the culture medium, and changes in gene expression were analyzed with real-time reverse transcription (RT) PCR. RESULTS: Link N alone did not promote MSC chondrogenesis. However, after MSCs were supplemented with Link N in chondrogenic differentiation medium, the quantity of GAG secreted into the culture medium, as well as aggrecan, COL2A1, and SOX9 gene expression, increased significantly. The gene expression of COL10A1 and osteocalcin (OC) were downregulated significantly. When MSCs were cultured in osteogenic differentiation medium, Link N supplementation led to a significant decrease in mineral deposition, and alkaline phosphatase (ALP), OC, and RUNX2 gene expression. CONCLUSIONS: Link N can enhance chondrogenic differentiation and downregulate hypertrophic and osteogenic differentiation of human MSCs. Therefore, in principle, Link N could be used to optimize MSC-mediated repair of the degenerated disc

Continued elevation of creatinine and uric acid in a male athlete: A case report

Whey protein and other protein-fortified supplements are frequently consumed as nutritional supplements to aid in muscle hypertrophy and myogenesis. This case presents a 36-year-old athletic male with elevated creatinine and uric acid levels during routine laboratory evaluation. The patient had no history of kidney disease, diabetes, or hypertension. It was revealed that the patient had been regularly consuming whey protein as a dietary supplement for 2 months. Given the potential association between the elevated creatinine and uric acid levels and the use of whey protein, the patient was advised to discontinue the supplement. The patient then switched to protein-fortified milk to mitigate the possible harmful connection between the dietary intake and the laboratory findings. However, despite the dietary change, the increased levels of creatinine and uric acid persisted. This observation suggests that the elevated levels may be attributed to chronic whey protein consumption along with high-protein dietary consumption

Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens

Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study

Abstract 82: Analysis of the role of MDM2 in regulation of cell cycle arrest through p21 pathways in LNCaP-MST cells using PCR array

Abstract Cell cycle checkpoints are imperative for assuring genomic fidelity and integrity during cell division. In normal cells, the cell cycle arrest occurs in response to nuclear DNA damage via activation and inactivation of a series of cell cycle regulatory molecules that can impact the transition from G1 to S phase and G2 to M phase. However, in cancerous cells, this process is disrupted resulting in uncontrolled cell proliferation and resistance to apoptosis. Therefore, cell cycle regulatory molecules are accepted as suitable targets for drug development and cancer treatment. It has been well known that overexpression of MDM2, a negative regulator of p53, will eventually lead to the inactivation of cell cycle control and loss of apoptotic ability in many tumors. In this study, we aimed to investigate the effectiveness of MDM2 inhibition in mediating cell cycle arrest through p53 dependent pathways by using the MDM2 transfected prostate cancer cells (LNCaP-MST). During our experiments the LNCaP-MST cells were treated for 24 hrs with 20 uM Nutlin-3, a small molecule inhibitor of MDM2/p53 interaction. The impact of Nutlin-3 treatment on the gene expression profile of LNCaP-MST cells was established by using the cell cycle pathway specific PCR array. Our study clearly demonstrates a significant increase of p21 gene expression after Nutlin-3 treatment, which indicates a possible restoration and release of the transcriptional activity of p53 in LNCaP-MST cells. In addition to the elevation of p21, a significant increase in the expression of Cyclin-Dependent Kinase 4 Inhibitor B (CDKN2B) along with multiple folds increase in the expression of Growth Arrest and DNA Damage 45 (GADD45A) genes were also found. These results clearly point towards efficient initiation of cell cycle arrest mechanisms in LNCaP-MST cells, possibly through p21 and CDKN2B mediated inhibition of the CDKs (cyclin dependent kinases). In addition, it appears that MDM2 inhibition may effectively block both G1 to S and G2 to M transition and cause DNA damage through apoptosis that could lead to the death of LNCaP-MST cells. Activation of the above outlined mechanisms following MDM2 inhibition is quite evident due to increased expression of GADD45A and decreased levels of anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. Our results offer convincing evidence towards the effectiveness of MDM2 inhibition in causing cell cycle arrest and apoptosis during cancer treatment. (This research was supported by the generous funds provided by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida) Citation Format: Khalid Alhazzani, Ali Alaseem, Thiagarajan Venkatesan, Appu Rathinavelu. Analysis of the role of MDM2 in regulation of cell cycle arrest through p21 pathways in LNCaP-MST cells using PCR array. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 82. doi:10.1158/1538-7445.AM2015-82</jats:p

Abstract 1535: Angiogenesis-related gene expression profile of a novel antiangiogenic agent F16 in human vascular endothelial cells

Abstract Angiogenesis is a key process in tumor propagation, progression, and metastasis. This process is tightly modulated by a wide range of growth factors, receptor tyrosine kinases, cytokines, matrix metalloproteinases, and transcription factors. Distinctively, vascular endothelial growth factor (VEGF) and their receptors have been identified as prominent stimulators of tumor angiogenesis. Therefore, inhibiting VEGF-induced tumor angiogenesis has been explored extensively for cancer therapy. In this context, F16, a novel small molecule possessing a unique molecular configuration to block VEGFR2, has been subjected to intensive preclinical investigations. The F16 molecule exhibits in vitro antiangiogenic activity via inhibiting endothelial cell proliferation, migration, and tube formation. In addition, F16 was found to significantly inhibit the in vivo angiogenesis in chick chorioallantoic membranes as well as in athymic nude mice with xenograft tumors. As a consequence of the antiangiogenic effects, F16 was able to effectively control the tumor growth in mice with xenograft tumors. In the present study, we aimed to comprehensively interrogate the impact of F16 treatment on the expression of a panel of angiogenesis-related genes to gain insight into the underlying molecular mode of action. We analyzed the expression of 84 genes that are known to be associated with angiogenesis in human umbilical vein endothelial cells (HUVECs). Our pilot study identified upregulation of some key genes in response to F16 treatment which include tissue inhibitor of metalloproteinase 1 (TIMP1), angiopoietin-like 4 (ANGPTL 4), chondromodulin 1 (LECT 1), and placenta growth factor (PIGF). On the other hand, several genes involved in promoting angiogenesis were downregulated, which include matrix metallopeptidase 9 (MMP9), integrin subunit beta 3 (ITGβ 3), insulin growth factor 1 (IGF 1), transforming growth factor alpha (TGF α), interleukin 6 (IL 6), leptin (LEP), thrombospondin -1, -2 (THBS -1, -2), tyrosine kinase (TEK), VEGF B and C. The differential genes expression related to pro- and anti-angiogenic growth factors coincide very well with our previous observation of F16 inhibiting endothelial cell proliferation, migration and tube formation. Based on the Gene Expression Profile (GEP) observed in our experiments, we speculate that F16 can induce TIMP1 which in turn could suppress the MMP9 signaling leading to the inhibition of endothelial cell migration. This disruption of TIMP1/MMP9 pathway offers an interesting foundation for functional studies that can be performed to confirm the role of F16 as a potential MMP9 inhibitor, which may provide extended benefits during the use of this drug for treating highly metastatic cancers. (This project was supported by The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Khalid Alhazzani, Ali Alaseem, Thiagarajan Venkatesan, Appu Rathinavelu. Angiogenesis-related gene expression profile of a novel antiangiogenic agent F16 in human vascular endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1535. doi:10.1158/1538-7445.AM2017-1535</jats:p

Abstract 309: Effect of histone deacetylase (HDAC) inhibitor on gene expression in MDM2 transfected prostate cancer cells

Abstract Deacetylation of histone gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression, and developmental events. HDACs catalyse the removal of the acetyl moiety from the lysine residues of proteins including the core nucleosomal histones. Through removal of critical acetyl groups from histones, HDACs can create a chromatin conformation that can prevent the transcription of genes that encode for proteins involved in cell cycle regulation. Thus together with histone acetyltransferases (HATs), HDACs regulate the level of acetylation and alter multitude of cellular functions and their characteristics. Several alterations of HDAC and HAT levels and activities have been found to be enacted by translocation, amplification, overexpression, or mutation of the relevant genes in a variety of cancers. In many cancer cell lines, overexpression or activation of the HDAC enzymes result in histone hypo-acetylation and consequent promotion of pro-cancerous mechanisms. Therefore, HDAC inhibitors represent a potential new class of antitumor agents with cytotoxic activity and the ability to regulate gene expression in tumor cells. In this study we evaluated the effects of Vorinostat (suberoylanilide hydroxamic acid), which is a potent inhibitor of HDAC activity, on cell cycle regulation in MDM2 (mouse double minute 2 homolog) overexpressing cells. MDM2 amplification or overexpression is found in many tumors that eventually lead to the inactivation of the cell cycle control and loss of pro-apoptotic functions through both p53 dependent and independent mechanisms. The PCR array, qRT-PCR, and western blot analysis of MDM2 overexpressing prostate cancer cells (LNCaP-MST), after treating with Nutlin-3 (20 µm) and 17-AAG (10 µm), was able to trigger p21 expression and down-regulation of BIRC5 (Baculoviral IAP Repeat Containing 5). Similarly, when we treated the MDM2 transfected LNCaP-MST cells with vorinostat (7.5 µm for 24 hrs), some of the above mentioned changes, similar to Nutlin-3 treatment, were observed. As a result of HDAC inhibition the mRNA levels of p21, p53 and TIMP-1 were significantly elevated, while the levels of BIRC5 was significantly down-regulated. Thus, treatment of MDM2 overexpressing cell lines with HDAC inhibitor resulted in activation of p21 and consequent decrease in cell proliferation due to resumption of cell cycle arrest. Our results with LNCaP-MST cells offer convincing evidence to suggest that the inhibition of HDAC can control cell proliferative signals in MDM2 overexpressing prostate cancer cells. (The generous support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged). Citation Format: Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Thanigaivelan Kanagasabai, Appu Rathinavelu. Effect of histone deacetylase (HDAC) inhibitor on gene expression in MDM2 transfected prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 309. doi:10.1158/1538-7445.AM2017-309</jats:p