Low back pain (LBP) is a common health issue worldwide with a huge economic burden on healthcare systems. In the United States alone, the cost is estimated to be $100 billion each year. Intervertebral disc degeneration is considered one of the primary causes of LBP. Moreover, the critical role of the vertebral endplates in disc degeneration and LBP is becoming apparent. Endplate abnormalities are closely correlated with disc degeneration and pain in the lumbar spine. Imaging modalities such as plain film radiography, computed tomography, and fluoroscopy are helpful but not very effective in detecting the causes behind LBP. Magnetic resonance imaging (MRI) can be used to acquire high-quality threedimensional images of the lumbar spine without using ionizing radiation. Therefore, it is increasingly being used to diagnose spinal disorders. However, according to the American College of Radiology, current referral and justification guidelines for MRI are not sufficiently clear to guide clinical practice. This review aimed to evaluate the role of MRI in diagnosing LBP by considering the correlative contributions of vertebral endplates. The findings of the review indicate that MRI allows for fine evaluations of endplate morphology, endplate defects, diffusion and perfusion properties of the endplate, and Modic changes. Changes in these characteristics of the endplate were found to be closely correlated with disc degeneration and LBP. The collective evidence from the literature suggests that MRI may be the imaging modality of choice for patients suffering from LBP.
Acute lymphoblastic leukemia (ALL) is an aggressive hematolymphoid malignancy and the prognosis is poor in adults with long-term survival of only 30% due to the high prevalence of high-risk subtypes. Therefore, there is an urgent need to develop novel treatment for ALL. Carfilzomib is a second-generation proteasome inhibitor which is more potent than its first-generation counterpart, bortezomib, with an excellent activity against bortezomib-resistant plasma cell myeloma. However, pre-clinical and clinical studies of carfilzomib in ALL are limited. Targeting DNA damage and mitotic defects of cancer cell is a major treatment strategy of cancer. WEE1 kinase prevents mitosis of cells with unrepaired DNA through inhibiting cyclin B. Pharmacological inhibition of WEE1 was effective in treating T-ALL with induction of DNA damage. Thus, targeting WEE1 kinase is an attractive approach of novel therapy in ALL. However, there are no studies to evaluate the mechanism of action of carfilzomib in ALL, especially in the aspect of DNA damage and mitotic catastrophe. Moreover, the role of WEE1 modulation by carfilzomib and its underlying mechanism has not been studied in ALL. In view of these unmet clinical needs and research gap, we conducted the study with the aims: 1). To show that carfilzomib induces DNA damage and mitotic catastrophe; 2). To show that carfilzomib induces WEE1 downregulation and delineate underlying mechanisms. ALL cell lines representing a spectrum of high-risk ALL including TOM-1, SEM, LOUCY, CCRF-CEM, KE-37 and PEER were treated with various doses of carfilzomib. Cell viability was reduced, and percentage of apoptotic cells was increased in a time and dose-dependent manner, measured by trypan blue assay and flow cytometry analysis by annexin V/PI staining respectively, upon treating with carfilzomib for 24 & 72 hours. Comet assay showed evidence of DNA damage after treating with carfilzomib for 24 hours. Fluorescence microscopy also demonstrated evidence of mitotic catastrophe upon treating with carfilzomib. Western blot analysis showed downregulation of WEE1 upon treatment of carfilzomib for 24 hours, with evidence of autophagy induction as shown by western blot analysis of LC3-1 and LC3-II. Quantitative PCR showed the upregulation of ER-stress related gene, CHOP while the mRNA level of WEE1 remained unchanged. Co-treatment of carfilzomib with autophagy inhibitor, bafilomycin A1, reversed the process of WEE1 downregulation. Herein, we proved that carfilzomib induced DNA damage and mitotic catastrophe with WEE1 downregulation. Moreover, carfilzomib trigger autophagy-mediated degradation of WEE1 in ALL via induction of ER-stress. The findings provide mechanistic insights of carfilzomib in ALL and rationalize the introduction of novel approach of combination treatment of carfilzomib with other DNA damaging agents. Citation Format: Chun-fung Sin, Rahman Ud Din, Anan Jiao, Kei-ching Yuen. Proteasome inhibitors induce DNA damage and mitotic catastrophe in acute lymphoblastic leukemia via autophagy-mediated degradation of WEE1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6199.
OBJECTIVES The study’s objective was to implement a methodological approach, "Acute Physiological and Chronic Health Evaluation II (APACHE-II),” to classify critically ill patients based on severity. METHODOLOGY A retrospective study design was conducted at Shaukat Khanum Memorial Cancer Hospital Lahore, Pakistan, from May 2019 to May 2020. A pilot study of 6 months was conducted by reviewing the medical record of 30 adult patients following convenient sampling after the approval of the proposal by ASRB/IRB of Shaukat Khanum hospital. The record of both male and female patients was studied, while no record of paediatric or adult patients outside the ICU was studied. Each patient’s severity score was obtained using the patient’s parameters with the help of the APACHE-II table. RESULTS Among the patients, three out of 30 scored 25, 29 and 30 on APACHE-II. These patients later passed away in ICU. This indicates that the mortality rate increases with an increase in the APACHE-II score. Thus, the scoring system is very beneficial in predicting adult ICU patients' mortality rate. CONCLUSION It is concluded that APACHE II is one of the best severity scoring systems in predicting the critical condition of patients.
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