A Comprehensive Two-Decade Analysis of Lymphoma Incidence Patterns in Saudi Arabia.

Background: Lymphomas account for approximately 10% of all cancer cases among the Saudi population. Even when separated, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are in the top ten most commonly diagnosed cancers among Saudi men and women. Despite the substantial cost of HL and NHL to public health, the resources to assess their impact are insufficient. This study provides a two-decade detailed assessment of lymphoma incidence trends in the Saudi population. Methods: Analysis of the Saudi Cancer Registry (SCR) data for various incidence metrics from 2001 to 2020 was conducted. Joinpoint regression analysis was further performed to investigate temporal trends globally and by age group, gender, and administrative region. Results: HL cases grew by 174.1%, whereas NHL cases increased by only 80% for that time period. The HL overall Age-Standardized Incidence Rate (ASR) increased by 100% for both genders combined but remained unchanged for NHL. The median age at diagnosis for HL (20-30 years) and NHL (46-57 years) was lower than in many other nations. Our model identified increasing trends for HL with annual percentage changes (APCs) of 2.94% (CI: 2.2-3.7) and 3.67% (CI: 2.6-4.7) for males and females, respectively. The rise was mainly among young groups under 40. On the contrary, the NHL cohort revealed notable declining tendencies. We discovered alarming rates of HL in Saudi Arabia's APC (2.23% for males and 3.88% for females) and ASR compared to other Western countries. Overall, the majority of the patients presented with advanced-stage disease at a younger age and with slight male predominance. Conclusions: The overall incidence of lymphoma (especially HL) has been rising among Saudis. Implementation of secondary and tertiary prevention measures, as well as management of modifiable risk factors, is warranted.

Prevalence and association of hyperuricemia with liver function in Saudi Arabia: a large cross-sectional study.

BACKGROUND: Hyperuricemia is linked to an increased risk of various chronic diseases, but data on the prevalence and association of hyperuricemia with liver function in Saudi Arabia are scarce. OBJECTIVES: Evaluate the prevalence, association, and risk measures of hyperuricemia and liver function in the Saudi population. DESIGN: Retrospective, cross-sectional analysis. SETTING: Database on large portion of Saudi population. PATIENTS AND METHODS: Laboratory data, age, and gender of the studied subjects were collected from Al Borg Diagnostics. Subjects were stratified, based on their uric acid (UA) levels, into three groups: hypouricemic, normouricemic, and hyperuricemic. The association of UA with liver enzymes was examined in all three groups. MAIN OUTCOME MEASURES: Association of serum UA levels with alanine transaminase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), and total bilirubin (TB). SAMPLE SIZE: 13 314 subjects. RESULTS: Our study showed that the prevalence of hyperuricemia in the Saudi population is 17.3% (20.3% in males and 15.1% in females). We also found a positive correlation between ALT, AST, and TB with UA levels. The risk of being hyperuricemic was significantly increased in individuals with elevated ALT, AST, and TB. Individuals with elevated ALT, AST, and total TB had a higher chance of having hyperuricemia than those with normal activity. Notably, ALT, AST, and TB had good discriminating capacity for hyperuricemia. CONCLUSIONS: Hyperuricemia is highly prevalent in the Saudi population and is associated with compromised liver function. However, further studies are needed to elucidate the mechanisms underlying these findings in large prospective cohort studies in different populations. LIMITATIONS: Lack of data on other potential confounding variables.

Association of the HALP Score with Dyslipidemia: A Large, Nationwide Retrospective Study.

Background and Objectives: Dyslipidemia is a major risk factor for cardiovascular disease (CVD). The identification of new biomarkers that may enhance the risk assessment of lipid abnormalities is a promising approach in improving risk prediction of CVD. There is no information on the association of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score with dyslipidemia. The aim of this study was to investigate the clinical utility of the HALP score in light of dyslipidemia. Materials and Methods: A retrospective analysis of 7192 subjects was initiated to assess the association between the HALP score and disturbed lipid markers. Medians were compared by Mann-Whitney U or Kruskal-Wallis tests and the diagnostic performance and risk assessment were calculated. Results: Median HALP score among all subjects was 53.3, with varying values between males and females. Notably, median HALP was significantly elevated in all forms of dyslipidemia and among males and females irrespective of age. The odds of having elevated HALP score values were significantly higher in all lipid abnormalities. Moreover, HALP score was significantly yet weakly correlated with lipid markers, while the highest diagnostic accuracy of the HALP score was observed with an elevated ratio of total cholesterol to high-density lipoprotein (TC/HDL) (area under the curve, AUC = 0.6411, p < 0.0001). The decision curve analysis (DCA) showed that the HALP score can reliably predict the presence of dyslipidemia. Conclusions: This study demonstrates that the HALP score is a novel, cost-effective index that is associated with a disturbed lipid profile. Further investigation of the nature of this association is needed.

AST and ALT APRI Scores and Dysglycemia in Saudi Arabia: A Retrospective Population Study.

BACKGROUND: Hyperglycemia is a common symptom of numerous conditions, most notably diabetes mellitus and Cushing's syndrome, and the liver plays a pivotal role in the regulation of glucose metabolism. The AST-platelet ratio index (AST APRI score) and ALT-platelet ratio index (ALT APRI score) are novel parameters whose association with circulating glucose levels remains poorly studied. METHODS: Laboratory data of 14,177 subjects were retrospectively analyzed for the association between AST and ALT APRI scores and fasting blood glucose (FBG) using the Mann-Whitney U and Kruskal-Wallis tests, Spearman's rank correlation coefficient, prevalence and odds ratio (OR) and ROC curve analysis. RESULTS: AST and ALT APRI scores showed progressive increases with FBG, and the mean FBG was significantly higher in subjects with high AST (104.9 ± 0.33 to 120.8 ± 3.27, p < 0.0001) and ALT (104.7 ± 0.34 to 111.6 ± 1.30, p < 0.0001) APRI scores. However, the AST APRI score but not the ALT APRI score was affected by age and gender. Notably, both elevated AST and ALT APRI scores were more prevalent in hyperglycemic subjects irrespective of gender and were associated with FBG, albeit through mediator variables. Increased AST (OR = 2.55, 95% CI: 1.46-2.06, p < 0.0001) and ALT (OR = 1.73, 95% CI: 1.46-2.06, p < 0.0001) APRI scores carried a significantly higher risk for hyperglycemia. Importantly, the ALT APRI score was superior to that of the AST APRI score in distinguishing hyperglycemic subjects. CONCLUSIONS: The AST and ALT APRI scores are inexpensive, novel markers of FBG and may serve as supportive evidence in the diagnosis and management of hyperglycemic conditions.

A Retrospective Analysis of the Association of Neutrophil-Lymphocyte Ratio (NLR) with Anemia in the Saudi Population.

Background: The link between inflammation and anemia is well established but fluctuations in the emerging inflammatory index, neutrophil-lymphocyte ratio (NLR), in anemic subjects remain ambiguous. The purpose of this study is to address the prevailing knowledge gaps regarding the association of NLR with anemia in the Saudi population. Methods: Laboratory results of NLR, C-reactive protein (CRP), and hemoglobin for 14,261 subjects were obtained from Al Borg Diagnostics and retrospectively analyzed. Means, risk measures, and the diagnostic performance of NLR for anemia were examined in age- and gender-wise comparisons. Results: NLR was significantly elevated in anemic individuals and those with high NLR had a significantly lower Hb concentration. Moreover, elevated NLR was more prevalent in anemic subjects (PR: 1.87, 95% CI: 1.46-2.40, p < 0.0001) and carried a greater risk for the condition (OR: 1.91, 95% CI: 1.47-2.48, p < 0.0001) as did CRP. These observations demonstrated distinct age- and gender-specific patterns. However, both parameters were of no value in the diagnosis of anemia as seen from receiver operating characteristic curves. Conclusions: Altogether, these findings indicate that elevated NLR is associated with anemia, which suggests its usefulness for monitoring rather than diagnosing anemia associated with inflammation in Saudi subjects. Further examination of this association in longitudinal studies is needed.

Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965.

SBI-0206965, originally identified as an inhibitor of the autophagy initiator kinase ULK1, has recently been reported as a more potent and selective AMP-activated protein kinase (AMPK) inhibitor relative to the widely used, but promiscuous inhibitor Compound C/Dorsomorphin. Here, we studied the effects of SBI-0206965 on AMPK signalling and metabolic readouts in multiple cell types, including hepatocytes, skeletal muscle cells and adipocytes. We observed SBI-0206965 dose dependently attenuated AMPK activator (991)-stimulated ACC phosphorylation and inhibition of lipogenesis in hepatocytes. SBI-0206965 (≥25 µM) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited insulin signalling, insulin-mediated/AMPK-independent glucose uptake, and AICA-riboside uptake. We performed an extended screen of SBI-0206965 against a panel of 140 human protein kinases in vitro, which showed SBI-0206965 inhibits several kinases, including members of AMPK-related kinases (NUAK1, MARK3/4), equally or more potently than AMPK or ULK1. This screen, together with molecular modelling, revealed that most SBI-0206965-sensitive kinases contain a large gatekeeper residue with a preference for methionine at this position. We observed that mutation of the gatekeeper methionine to a smaller side chain amino acid (threonine) rendered AMPK and ULK1 resistant to SBI-0206965 inhibition. These results demonstrate that although SBI-0206965 has utility for delineating AMPK or ULK1 signalling and cellular functions, the compound potently inhibits several other kinases and critical cellular functions such as glucose and nucleoside uptake. Our study demonstrates a role for the gatekeeper residue as a determinant of the inhibitor sensitivity and inhibitor-resistant mutant forms could be exploited as potential controls to probe specific cellular effects of SBI-0206965.

A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner.

Activation of AMP-activated protein kinase (AMPK) is considered a valid strategy for the treatment of type 2 diabetes. However, despite the importance of adipose tissue for whole-body energy homeostasis, the effect of AMPK activation in adipocytes has only been studied to a limited extent and mainly with the AMP-mimetic 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR), which has limited specificity. The aim of this study was to evaluate the effect of the allosteric AMPK activators A-769662 and 991 on glucose uptake in adipocytes. For this purpose, primary rat or human adipocytes, and cultured 3T3-L1 adipocytes, were treated with either of the allosteric activators, or AICAR, and basal and insulin-stimulated glucose uptake was assessed. Additionally, the effect of AMPK activators on insulin-stimulated phosphorylation of Akt and Akt substrate of 160 kDa was assessed. Furthermore, primary adipocytes from ADaM site binding drug-resistant AMPKß1 S108A knock-in mice were employed to investigate the specificity of the drugs for the observed effects. Our results show that insulin-stimulated adipocyte glucose uptake was significantly reduced by A-769662 but not 991, yet neither activator had any clear effects on basal or insulin-stimulated Akt/AS160 signaling. The use of AMPKß1 S108A mutant-expressing adipocytes revealed that the observed inhibition of glucose uptake by A-769662 is most likely AMPK-independent, a finding which is supported by the rapid inhibitory effect A-769662 exerts on glucose uptake in 3T3-L1 adipocytes. These data suggest that AMPK activation per se does not inhibit glucose uptake in adipocytes and that the effects of AICAR and A-769662 are AMPK-independent.

Regulation of nutrient uptake by AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is a key regulator of energy balance at both the cellular and whole-body level. AMPK acts to stimulate ATP production and reduce ATP consumption when cellular ATP levels fall, thereby normalizing energy balance. Given the central role of AMPK in cellular carbohydrate and lipid metabolism, AMPK activation has been proposed to be a therapeutic target for conditions associated with dysfunctional nutrient metabolism including obesity, type 2 diabetes, hepatic steatosis, cardiovascular diseases and cancer. One way by which increased ATP production can be achieved is by increasing the supply of nutrient substrates. In the 1990s, AMPK activation was demonstrated to stimulate glucose uptake in striated muscle, thereby improving substrate supply for ATP production. Subsequently AMPK activation was postulated to underlie the increase in glucose uptake that occurs during muscle contraction. More recently, however, several lines of evidence have demonstrated that AMPK activation is unlikely to be required for contraction-mediated glucose uptake. Furthermore, despite the importance of AMPK in cellular and whole-body metabolism, far fewer studies have investigated either the role of AMPK in glucose uptake by non-muscle tissues or whether AMPK regulates the uptake of fatty acids. In the present review, we discuss the role of AMPK in nutrient uptake by tissues, focusing on glucose uptake out with muscle and fatty acid uptake.