A New Benzofuran Glucoside from Ficus Tikoua Bur

From the water-soluble portion of the methanol extract of stems of Ficus tikoua Bur., a new benzofuran glucoside, named 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-d-glucopyranoside (1), together with one known benzofuran glucoside (2) were isolated. Their structures were elucidated by 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy and HRMS techniques. The antioxidant activities of the isolated compounds were assayed based on the scavenging activities of DPPH free radical. Compounds 1 and 2 exhibited moderate antioxidant activities, and the IC50 values were 242.8 μg·mL−1 and 324.9 μg·mL−1, respectively

Comprehensive molecular and clinicopathological characterization of breast cancer metastasis - emphasis on invasive lobular carcinoma

Metastatic breast cancer (MBC) has been the main cause of death in breast cancer patients, demonstrating a major public health burden. Estrogen receptor-alpha (ER; ESR1) is expressed in nearly 70% of breast tumors and has been a key target for endocrine therapy. Yet, 20-40% of patients eventually develop relapse. Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer, characterized by near universal expression of ER, and by frequent late recurrences. The goal of my studies was to identify genetic changes that might cause endocrine resistance and metastases, with emphasis on ILC. While many studies have identified ESR1 mutations in recurrent tumors, less is known about changes in ESR1 DNA copy number (CN) changes and their clinical relevance. First, sensitive nanoString-technology was used to comprehensively investigate the role of these alterations in MBC. Our analysis identified substantial rates of ESR1 gains and amplifications in MBC that were of metastatic-site tropism and showed significant association with poor overall survival. Additionally, mutually exclusive amplifications of CCND1 and deletions of CDKN1B and CDKN2A were identified, potentially defining a subset of patients with improved response to CDK4/6 inhibition. I also identified frequent ESR1 amplifications in ILC, and they were significantly enriched in tumors with recurrence and showed association with recurrence-free survival. CN analysis also discovered a unique group of tumors negative for HER2 by IHC characterized by HER2 DNA amplifications, which correlated with high mRNA and protein expression, and enrichment of molecular HER2 signature. Lastly, in addition to clinicopathological evaluation, I utilized RNA-seq approach to understand transcriptomic changes involved in unique ILC metastasis to the ovaries. Our analyses revealed unique transcriptomic alterations in WNT, glutamate/calcium receptors, and MAPK/ERK pathways. Analysis of clinically actionable genes identified MYCN as potential mediator of endocrine resistance. Using targeted sequencing, I further validated previously reported PIK3CA and FOXA1 mutations, and identified novel NCOR1 mutations enriched in the metastases. Collectively, these studies address distinct molecular changes involved in endocrine resistance and metastasis. Such findings are of public health significance, as they can serve as novel therapeutic targets for the leading cause of death in women

The Role of Immune Checkpoint Inhibitors in Cancer Therapy

Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions

Breast Cancer Incidence Patterns in the Saudi Female Population: A 17-Year Retrospective Analysis

Background and Objectives: Breast cancer is considered the most commonly diagnosed type of cancer among women globally and in Saudi Arabia. This study aimed to assess breast cancer incidence patterns and trends among the Saudi female population. Materials and Methods: Breast cancer incidence parameters were obtained from the Saudi Cancer Registry (SCR). The data were retrospectively analyzed for the period from 2001 to 2017 to investigate changes in incidence rates. Temporal trends were also analyzed through joinpoint regression analysis and were dissected by age groups and administrative regions. Results: During the specified period, breast cancer jumped by 55% to constitute 30.9% of all cancer cases among Saudi females. The median age at diagnosis increased to reach 51 years at the end of that period, with an overall increase of 6.3%. The overall Age-Standardized Incidence Rate (ASR) escalated by 151.7% from 11.8/100,000 to 29.7/100,000 population for that period. The Eastern region noticeably had the highest ASR and peaked at 52.2/100,000 population. The joinpoint analysis of the ASR showed increased trends, with an annual percent change (APC) of 5.13% (p p p Conclusions: Our analysis indicates increased breast cancer incidence in Saudi Arabia with an alarming pace. With the existing trend, it is expected that Saudi Arabia will continue to display an increase in breast cancer incidence. Long-term preventive measures and more effective screening strategies are warranted to alleviate the burden of the disease

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 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

Induction of hemolysis and eryptosis by occupational pollutant nickel chloride is mediated through calcium influx and p38 MAP kinase signaling

ObjectivesNickel (Ni) is an abundant environmental hazard and an occupational pollutant. Exposure to Ni compounds is prevalent in electroplating workers and in the printing industry, among others. The toxicity of Ni manifests as dermatological, gastrointestinal, respiratory, allergic, and cardiovascular symptoms. In particular, hyperbilirubinemia and reticulocytosis have been detected in intoxicated subjects; an observation possibly implicating selective red blood cell (RBC) toxicity. Herein, the interaction of nickel chloride (NiCl2) with human RBCs and associated molecular mechanisms are described.Material and MethodsCells from healthy donors were incubated for 24 h at 37°C in the presence or absence of 0.5‒10 mM of NiCl2, and cytotoxicity was determined through hemoglobin leakage by colorimetry under different experimental conditions. Eryptotic markers were also identified by flow cytofluorometry using Annexin-V-FITC tagging for phosphatidylserine (PS) exposure, light scatter properties for cellular dimensions, Fluo4/AM labeling for intracellular calcium, and H2DCFDA staining for reactive oxygen species (ROS). Additionally, small molecule inhibitors were used to probe the signaling pathways involved.ResultsIt was found that NiCl2 at 10 mM caused profound intracellular calcium overload and significant calcium-dependent hemolysis. Also, NiCl2 reduced forward scatter and increased side scatter, Annexin-positive cells, and ROS levels. Importantly, NiCl2-induced hemolysis was significantly attenuated by the exclusion of extracellular calcium, and in the presence of p38 MAP kinase (MAPK) inhibitor SB203580.ConclusionsIt is concluded that NiCl2 induces p38 MAPK-dependent hemolysis, and stimulates the canonical features of premature eryptosis. This report presents the first description of the molecular mechanisms underlying the hemolytic and eryptotic potential of NiCl2 and, thus, may explain changes in hematological parameters observed in poisoning victims

Comprehensive Retrospective Analysis of Colorectal Cancer Incidence Patterns in Saudi Arabia

Colorectal cancer (CRC) is the commonest cancer in Saudi males and the third most common in Saudi females. Although CRC represents a major public health challenge, the resources to evaluate its burden are inadequate. This study aims to elucidate the magnitude of CRC incidence trends in the Saudi population by age, gender, and administrative region. Data for multiple incidence measures were analyzed from the Saudi Cancer Registry (SCR) retrospectively from 2001 to 2018. Temporal trends were further analyzed by age group, gender, administrative region, and globally using joinpoint regression analysis. The number of CRC cases climbed by 335.6% and the disease increased by 56.4% to comprise 12.2% of all cancers cases. The age-standardized incidence rate (ASR) increased by 152% overall, and the median age at diagnosis peaked at 60 and 58 years for males and females, respectively. Riyadh and the Eastern Region had the highest ASR for both genders, peaking at 21.8 and 19.2 for males and 17.4 and 16.5 for females per 100 K population. Our prediction model identified growing trends with annual percentage changes (APCs) of 4.59% in males (CI: 3.1–6.1) and 3.91% among females (CI: 2.4–5.5). Males above 75 years had the highest APC (7.9%, CI: 5.3–10.7), whereas the highest APC among females was found in the age group 70–74 (5.4%, CI: 2.8–8). Globally, APC was the highest for both genders compared to selected countries. CRC incidence is increasing alarmingly in Saudi Arabia and is projected to continue. There is a need for better screening strategies, preventative measures, and awareness-building

Patterns of 25-Hydroxyvitamin D3, Calcium Status, and Anemia in the Saudi Population: A Cross-Sectional Study

Background: Emerging evidence suggests an intricate relationship between vitamin D, Ca2+, and inflammation-driven anemia. We, thus, investigated the patterns of serum 25(OH)D3, Ca2+, ferritin, and iron in healthy and anemic members of the Saudi population. Methods: A population-based, retrospective, cross-sectional study was designed to analyze data for 14,229 subjects, aged 3–110 years, obtained from Al-Borg Medical Laboratories, over a six-year period (2014–2020). Gender and age differences were analyzed for 25(OH)D3, Ca2+, hemoglobin, ferritin, and iron. Results: Vitamin D deficiency was extremely prevalent (98.47%) irrespective of age or gender, despite an increasing trend with age, in clear contrast to serum Ca2+. Ferritin was significantly lower in young adult and adult females, compared to elderly females, whereas iron was significantly reduced in females; in particular, adult females compared to young adults or elderly adults. Only anemic adult males had significantly lower 25(OH)D3, while Ca2+ was consistently significantly diminished in anemics of all age groups, independent of gender. Notably, hypocalcemic subjects were 2.36 times more likely to be anemic. Moreover, ferritin, but not iron, was significantly diminished in anemics, which was only evident in young adults and adults. However, both ferritin and iron showed positive correlation with hematocrit, hemoglobin, MCH, MCHC, and MCV. Conclusions: Despite being significantly lower in anemics, 25(OH)D3 is not particularly associated with anemia, while hypocalcemia is associated with an increased risk for anemia. Assessment of vitamin D and Ca2+ status may be valuable in the clinical management of anemia in the Saudi population

A Major Diplotaxis harra-Derived Bioflavonoid Glycoside as a Protective Agent against Chemically Induced Neurotoxicity and Parkinson’s Models; In Silico Target Prediction; and Biphasic HPTLC-Based Quantification

Oxidative stress and chronic inflammation have a role in developing neurodegenerative diseases such as Parkinson’s disease (PD) and inflammatory movement disorders such as rheumatoid arthritis that affect millions of populations. In searching for antioxidant and anti-inflammatory molecules from natural sources that can counteract neurodegenerative diseases and arthritis, the flavonoid-rich extract of Diplotaxis harra (DHE) was selected based on its in vitro antioxidant and anti-inflammatory activities. DHE could inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages from 100% to the level of 28.51 ± 18.67 and 30.19 ± 5.00% at 20 μg/mL, respectively. A TLC bioautography of DHE fractions using 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) led to the isolation of a major antioxidant compound which was identified by X-ray diffraction analysis as isorhamnetin-3-O-β-D-glucoside (IR3G). IR3G also exhibited a potent anti-inflammatory activity, particularly by suppressing the upregulation of iNOS expression, similar to that of dexamethasone (DEX) at 10 μM to the level of 35.96 ± 7.80 and 29.34 ± 6.34%, respectively. Moreover, IR3G displayed a strong neuroprotectivity (>60% at 1.0−4–1.0−3 μM) against 6-hydroxydopamine (6-OHDA)-challenged SHSY5Y neuroblastoma, an in vitro model of dopaminergic neurons for Parkinson’s disease (PD) research. Accordingly, the in vivo anti-Parkinson potentiality was evaluated, where it was found that IR3G successfully reversed the 6-OHDA-induced locomotor deficit in a zebrafish model. A study of molecular docking and molecular dynamic (MD) simulation of IR3G and its aglycone isorhamnetin (IR) against human acetylcholine esterase (AChE), monoamine oxidase B (MAO-B), and Polo-like kinase-2 (PLK2) was performed and further outlined a putative mechanism in modulating neurodegenerative diseases such as PD. The free radical scavenging, anti-inflammatory through anti-iNOS and anti-COX-2 expression, and neuroprotective activities assessed in this study would present partial evidence for the potentiality of D. harra-derived IR3G as a promising natural therapeutic agent against neurodegenerative diseases and inflammatory arthritis. Finally, a biphasic HPTLC method was developed to estimate the biomarker IR3G in D. harra quantitatively

Monocyte–Lymphocyte Ratio and Dysglycemia: A Retrospective, Cross-Sectional Study of the Saudi Population

Background: Abnormalities in fasting blood glucose (FBG) resulting in hypoglycemia (OG), impaired fasting glycemia (IFG), or hyperglycemia (HG) arise from disordered metabolic regulation caused in part by inflammation. To date, there is a dearth of evidence regarding the clinical utility of the monocyte–lymphocyte ratio (MLR), an emerging inflammatory index, in the management of dysglycemia. Methods: This retrospective, cross-sectional study explored MLR fluctuations as a function of glycemic control in 14,173 Saudi subjects. Data collected from 11 August 2014 to 18 July 2020 were retrieved from Al-Borg Medical Laboratories. Medians were compared by Mann–Whitney U or Kruskal–Wallis tests and the prevalence, relative risk (RR), and odds ratio (OR) were calculated. Results: MLR was significantly elevated in IFG (p < 0.0001) and HG (p < 0.05) groups compared to the normoglycemia (NG) group, and individuals with elevated MLR (>0.191) had significantly increased FBG (p < 0.001). The risk of IFG (RR = 1.12, 95% CI: 1.06–1.19, p < 0.0002) and HG (RR = 1.10, 95% CI: 1.01–1.20, p < 0.0216) was significantly increased if MLR was elevated, and individuals with elevated MLR were 1.17 times more likely to have IFG (OR = 1.17, 95% CI: 1.08–1.26, p < 0.0002) and 1.13 times more likely to have HG (OR = 1.13, 95% CI: 1.02–1.24, p < 0.0216). Conclusion: Elevated MLR is correlated with and carries a greater risk for IFG and HG. However, large prospective cohort studies are needed to establish the temporal relationship between MLR and FBG and to examine the prognostic value of this novel marker