ANO4 Expression Is a Potential Prognostic Biomarker in Non-Metastasized Clear Cell Renal Cell Carcinoma

Background: Over the past decade, transcriptome profiling has elucidated many pivotal pathways involved in oncogenesis. However, a detailed comprehensive map of tumorigenesis remains an enigma to solve. Propelled research has been devoted to investigating the molecular drivers of clear cell renal cell carcinoma (ccRCC). To add another piece to the puzzle, we evaluated the role of anoctamin 4 (ANO4) expression as a potential prognostic biomarker in non-metastasized ccRCC. Methods: A total of 422 ccRCC patients with the corresponding ANO4 expression and clinicopathological data were obtained from The Cancer Genome Atlas Program (TCGA). Differential expression across several clinicopathological variables was performed. The Kaplan–Meier method was used to assess the impact of ANO4 expression on the overall survival (OS), progression-free interval (PFI), disease-free interval (DFI), and disease-specific survival (DSS). Univariate and multivariate Cox logistic regression analyses were conducted to identify independent factors modulating the aforementioned outcomes. Gene set enrichment analysis (GSEA) was used to discern a set of molecular mechanisms involved in the prognostic signature. Tumor immune microenvironment was estimated using xCell. Results: ANO4 expression was upregulated in tumor samples compared to normal kidney tissue. Albeit the latter finding, low ANO4 expression is associated with advanced clinicopathological variables such as tumor grade, stage, and pT. In addition, low ANO4 expression is linked to shorter OS, PFI, and DSS. Multivariate Cox logistic regression analysis identified ANO4 expression as an independent prognostic variable in OS (HR: 1.686, 95% CI: 1.120–2.540, p = 0.012), PFI (HR: 1.727, 95% CI: 1.103–2.704, p = 0.017), and DSS (HR: 2.688, 95% CI: 1.465–4.934, p = 0.001). GSEA identified the following pathways to be enriched within the low ANO4 expression group: epithelial–mesenchymal transition, G2-M checkpoint, E2F targets, estrogen response, apical junction, glycolysis, hypoxia, coagulation, KRAS, complement, p53, myogenesis, and TNF-α signaling via NF-κB pathways. ANO4 expression correlates significantly with monocyte (ρ = −0.1429, p = 0.0033) and mast cell (ρ = 0.1598, p = 0.001) infiltration. Conclusions: In the presented work, low ANO4 expression is portrayed as a potential poor prognostic factor in non-metastasized ccRCC. Further experimental studies should be directed to shed new light on the exact molecular mechanisms involved.The article processing charges were funded jointly by Qatar National Library and Qatar University

Phenethyisoquinoline alkaloids from the leaves of Androcymbium palaestinum

Thirteen compounds were isolated from the methanolic extract of the leaves of Androcymbium palaestinum Baker (Colchicaceae). Of these, three were new, two were new natural products, and eight were known. The new isolated compounds were (+)-1-demethylandrocine (5), (−)-andropalaestine (8), and (+)-2-demethyl-β-lumicolchicone (10), while the new natural products were (+)-O-methylkreysigine-N-oxide (3) and (+)-O,O-dimethylautumnaline (9). Moreover, two known compounds are reported for the first time from this species, specifically (−)-colchicine (11) and (−)-3-demethyldemecolcine (13). The structures of the isolated compounds were elucidated using a series of spectroscopic and spectrometric techniques, principally HRESIMS, 1D-NMR (1H and 13C NMR) and 2D-NMR (COSY, edited-HSQC, and HMBC). ECD spectroscopy was used for assigning the absolute configurations of compounds 3, 5, and 10. The cytotoxic activities of the isolated compounds were evaluated using the MDA-MB-435 (melanoma), MDA-MB-231 (breast), and OVCAR3 (ovary) cancer cell lines. Compound 11 was the most potent against all tested cell lines, with IC50 values of 12, 95 and 23 nM, respectively.This research was supported, in part, by the Deanship of Research, Jordan University of Science and Technology, Irbid, Jordan (Grant No. 258/2017) and the National Cancer Institute/National Institutes of Health, Bethesda, MD, USA via P01 CA125066. We thank Dr. L. Flores Bocanegra, J. M. Gallagher, Z. Y. Al Subeh, and Dr. N. D. Paguigan from UNCG for technical help and valuable suggestions. This work was performed in part at the Joint School of Nanoscience and Nanoengineering, a member of the Southeastern Nanotechnology Infrastructure Corridor (SENIC) and National Nanotechnology Coordinated Infrastructure (NNCI), which is supported by the National Science Foundation (Grant ECCS-1542174)

Evaluation of the Wound Healing Potential of Hypericum triquetrifolium Turra: An Experimental Animal Study and Histopathological Examination

The wound healing potential of the aerial parts of Hypericum triquetrifolium Turra (Hypericaceae) was evaluated using an in vivo excision wound model in rats. Adult male Sprague Dawley rats were randomly assigned into seven groups; blank vehicles (olive oil and petroleum jelly), negative control, treatments [H. triquetrifolium ethanolic extract in petroleum jelly (5% and 10%) and H. triquetrifolium olive oil macerate (100 and 200 g/L)], and positive control (MEBO). Treatments were applied topically once daily until the wounds had completely healed. Wound areas and contraction rates were calculated, and full-thickness samples of the healed skin were collected for histopathological examination. H. triquetrifolium ointment (5%) showed the best wound healing activity with statistically significant differences when compared with the MEBO, petroleum jelly, and the negative control groups. Tissue sections were histopathologically examined in terms of re-epithelialization, granulation tissue development, collagen deposition, inflammatory cell infiltration, angiogenesis, and ulcer formation to support the in vivo excision wound model findings. H. triquetrifolium ointment (5%) showed the best histopathological scores in both re-epithelialization and ulcer formation. For quality control purposes, a high-performance liquid chromatography (HPLC) method was used to quantify key marker compounds in the extract, namely hypericin and rutin which showed a content of 0.64% and 4.46% (w/w), respectively. Based on the experimental results, H. triquetrifolium ointment (5%) exhibits remarkable wound healing properties at various stages of the wound healing process. Further investigations to prove its safety and efficacy in different types of wounds and to uncover its cellular mechanisms are warranted.This work was funded by the Deanship of Research, Jordan University of Science and Technology (Grant number: 122/2017), and Qatar University

Cyclin dependent kinase inhibitor 3 (CDKN3) upregulation is associated with unfavorable prognosis in clear cell renal cell carcinoma and shapes tumor immune microenvironment: A bioinformatics analysis

Cell cycle regulatory proteins plays a pivotal role in the development and progression of many human malignancies. Identification of their biological functions as well as their prognostic utility presents an active field of research. As a continuation of the ongoing efforts to elucidate the molecular characteristics of clear cell renal cell carcinoma (ccRCC); we present a comprehensive bioinformatics study targeting the prognostic and mechanistic role of cyclin-dependent kinase inhibitor 3 (CDKN3) in ccRCC. The ccRCC cohort from the Cancer Genome Atlas Program was accessed through the UCSC Xena browser to obtain CDKN3 mRNA expression data and their corresponding clinicopathological variables. The independent prognostic signature of CDKN3 was evaluated using univariate and multivariate Cox logistic regression analysis. Gene set enrichment analysis and co-expression gene functional annotations were used to discern CDKN3-related altered molecular pathways. The tumor immune microenvironment was evaluated using TIMER 2.0 and gene expression profiling interactive analysis. CDKN3 upregulation is associated with shortened overall survival (hazard ratio [HR] = 2.325, 95% confident interval [CI]: 1.703–3.173, P < .0001) in the Cancer Genome Atlas Program ccRCC cohort. Univariate (HR: 0.426, 95% CI: 0.316–0.576, P < .001) and multivariate (HR: 0.560, 95% CI: 0.409–0.766, P < .001) Cox logistic regression analyses indicate that CDKN3 is an independent prognostic variable of the overall survival. High CDKN3 expression is associated with enrichment within the following pathways including allograph rejection, epithelial–mesenchymal transition, mitotic spindle, inflammatory response, IL-6/JAK/STAT3 signaling, spermatogenesis, TNF-α signaling via NF-kB pathway, complement activation, KRAS signaling, and INF-γ signaling. CDKN3 is also associated with significant infiltration of a wide spectrum of immune cells and correlates remarkably with immune-related genes. CDKN3 is a poor prognostic biomarker in ccRCC that alters many molecular pathways and impacts the tumor immune microenvironment.Scopu

Molecular Characterization of Carbapenem-Resistant Acinetobacter baumannii Isolated from Intensive Care Unit Patients in Jordanian Hospitals

Acinetobacter baumannii is a common cause of healthcare-associated infections (HAI) worldwide, mostly occurring in intensive care units (ICUs). Extended-spectrum beta lactamases (ESBL)-positive A. baumannii strains have emerged as highly resistant to most currently used antimicrobial agents, including carbapenems. The most common mechanism for carbapenem resistance in this species is &beta;-lactamase-mediated resistance. Carbapenem-hydrolyzing class D oxacillinases are widespread among multidrug-resistant (MDR) A. baumannii strains. The present study was conducted to determine the presence and distribution of blaOXA genes among multidrug-resistant A. baumannii isolated from ICU patients and genes encoding insertion sequence (IS-1) in these isolates. Additionally, the plasmid DNA profiles of these isolates were determined. A total of 120 clinical isolates of A. baumannii from various ICU clinical specimens of four main Jordanian hospitals were collected. Bacterial isolate identification was confirmed by biochemical testing and antibiotic sensitivity was then assessed. PCR amplification and automated sequencing were carried out to detect the presence of blaOXA-51, blaOXA-23, blaOXA-24, and blaOXA-58 genes, and ISAba1 insertion sequence. Out of the 120 A. baumannii isolates, 95% of the isolates were resistant to three or more classes of the antibiotics tested and were identified as MDR. The most frequent resistance of the isolates was against piperacillin (96.7%), cephalosporins (97.5%), and &beta;-lactam/&beta;-lactamase inhibitor combinations antibiotics (95.8%). There were 24 (20%) ESBL-producing isolates. A co-existence of blaOXA-51 gene and ISAba1 in all the 24 ESBL-producing isolates was determined. In addition, in the 24 ESBL-producing isolates, 21 (87.5%) carried blaOXA-51 and blaOXA-23 genes, 1 (4.2%) carried blaOXA-51 and blaOXA-24, but all were negative for the blaOXA-58 gene. Plasmid DNA profile A and profile B were the most common (29%) in ESBL-positive MDR A. baumannii isolates while plasmid DNA profile A was the most common in the ESBL-negative isolates. In conclusion, there was an increase in prevalence of MDR-A. baumannii in ICU wards in Jordanian hospitals, especially those having an ESBL phenotype. Thus, identification of ESBL genes is necessary for the surveillance of their transmission in hospitals

Vitreous Levels of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor in Patients with Proliferative Diabetic Retinopathy: A Clinical Correlation

Background: The global epidemic status of diabetic retinopathy (DR) and its burden presents an ongoing challenge to health-care systems. It is of great interest to investigate potential prognostic biomarkers of DR. Such markers could aid in detecting early stages of DR, predicting DR progression and its response to therapeutics. Herein, we investigate the prognostic value of intravitreal concentrations of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) in a DR cohort. Materials and methods: Vitreous sample acquisition was conducted at King Abdullah University Hospital (KAUH) between December 2020 and June 2022. Samples were obtained from any patient scheduled to undergo a pars plana vitrectomy (PPV) for any indication. Included patients were categorized into a DR group or a corresponding non-diabetic (ND) control group. Demographics, clinicopathological variables, standardized laboratory tests results, and optical coherence tomography (OCT) data were obtained for each included individual. Intravitreal concentrations of VEGF and PDGF were assessed using commercial enzyme-linked immunosorbent assay (ELISA). Results: A total of 80 eyes from 80 patients (DR group: n = 42 and ND control group: n = 38) were included in the analysis. The vitreous VEGF levels were significantly higher in the DR group compared to the ND control group (DR group 5744.06 ± 761.5 pg/mL versus ND control group 817.94 ± 403.1 pg/mL, p = 0.0001). In addition, the vitreous PDGF levels were also significantly higher in the DR group than those in the ND control group (DR group 4031.51 ± 410.2 pg/mL versus ND control group 2691.46 ± 821.0 pg/mL, p = 0.001). Bassline differences between test groups and clinical factors impacting VEGF and PDGF concentrations were investigated as well. Multiple regression analysis indicated PDGF as the sole independent risk factor affecting best-corrected visual acuity (BCVA) at the last follow-up visit: the higher the PDGF vitreous levels, the worst the BCVA. Conclusions: Vitreous concentrations of VEGF and PDGF are correlated with DR severity and may exhibit a possible prognostic potential value in DR. Further clinical and experimental data are warranted to confirm the observed findings and to help incorporate them into daily practice

Cesarean scar ectopic partial molar pregnancy: A case report and a review of literature

A scar ectopic pregnancy exhibiting hydatidiform features is an extremely rare and clinically challenging entity. Delayed diagnosis and failure to treat such cases promptly can lead to devastating consequences. In this report, we present a case of cesarean scar ectopic partial molar pregnancy in a 37-year-old woman who presented with complaints of vaginal discharge with streaks of blood and lower abdominal pain. Diagnostic laparoscopy revealed an abnormal mass of brown soft tissue in the anterior wall of the uterus, measuring 13.0 × 9.0 × 2.0 cm, raising suspicion (in the context of elevated serum human chorionic gonadotropin levels) of a scar ectopic pregnancy. Open laparotomy was performed, and the scar ectopic mass was successfully removed. The histologic examination of the tissue revealed a partial hydatidiform mole. The patient experienced a full recovery postoperatively, with serum human chorionic gonadotropin levels gradually declining to normal values. This report is unique in its presentation of the clinicopathological features of cesarean scar ectopic molar pregnancy and the successful management of the condition

Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) comprises a group of aggressive and heterogeneous breast carcinoma. Chemotherapy is the mainstay for the treatment of triple-negative tumors. Nevertheless, the success of chemotherapeutic treatments is limited by their toxicity and development of acquired resistance leading to therapeutic failure and tumor relapse. Hence, there is an urgent need to explore novel targeted therapies for TNBC. Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that are key regulators of intracellular signaling pathways controlling cell proliferation, differentiation, survival, and motility. Aberrant activity and/or expression of several types of RTKs have been strongly connected to tumorigenesis. RTKs are frequently overexpressed and/or deregulated in triple-negative breast tumors and are further associated with tumor progression and reduced survival in patients. Therefore, targeting RTKs could be an appealing therapeutic strategy for the treatment of TNBC. This review summarizes the current evidence regarding the antitumor activity of RTK inhibitors in preclinical models of TNBC. The review also provides insights into the clinical trials evaluating the use of RTK inhibitors for the treatment of patients with TNBC

Natural resorcylic acid lactones: A chemical biology approach for anticancer activity

Resorcylic acid lactones (RALs) are fungal polyketides that consist of a β-resorcylic acid residue (2,4-dihydroxybenzoic acid) embedded in a macrolactone ring. RALs exhibit a broad range of biological activities, including anticancer activities. Following discovery of the selective Hsp90 inhibition activity of radicicol, the kinase inhibition activity of hypothemycin, monocillin II, 5Z-7-oxo-zeaenol, and L-783,277 RALs, and the nuclear factor kappa B (NF-κB) inhibition activity of the RAL zearalenone, have attracted great attention as potential therapeutics for cancer treatment. In this minireview, we focus on natural RALs that possess cytotoxic activities [IC50 values < 10 μM (or 4–5 μg/ml)], discussing their structures, isolation, occurrence, biological activities, and anticancer molecular mechanisms.This work is supported by funding from the Medical Research Center (grant no. MRC-01-21-301 (SU)), Hamad Medical Corporation, Doha, Qatar. The authors acknowledge Qatar National Library, Doha, Qatar for supporting Open Access funding for this article

The Prognostic Utility of Lymphocyte-Based Measures and Ratios in Chemotherapy-Induced Febrile Neutropenia Patients following Granulocyte Colony-Stimulating Factor Therapy

Background and Objectives: Chemotherapy-induced febrile neutropenia is the most widespread oncologic emergency with high morbidity and mortality rates. Herein we present a retrospective risk factor identification study to evaluate the prognostic role of lymphocyte-based measures and ratios in a cohort of chemotherapy-induced febrile neutropenia patients following granulocyte colony-stimulating factor (G-CSF) therapy. Materials and Methods: The electronic medical records at our center were utilized to identify patients with a first attack of chemotherapy-induced febrile neutropenia and were treated accordingly with G-CSF between January 2010 to December 2020. Patients&rsquo; demographics and disease characteristics along with laboratory tests data were extracted. Prognosis-related indicators were the absolute neutrophil count (ANC) at admission and the following 6 days besides the length of stay and mortality rate. Results: A total of 80 patients were enrolled, which were divided according to the absolute lymphocyte count at admission into two groups, the first includes lymphopenia patients (n = 55) and the other is the non-lymphopenia group (n = 25) with a cutoff point of 700&thinsp;lymphocytes/&mu;L. Demographics and baseline characteristics were generally insignificant among the two groups but the white blood cell count was higher in the non-lymphopenia group. ANC, neutrophils percentage and ANC difference in reference to admission among the two study groups were totally insignificant. The same insignificant pattern was observed in the length of stay and the mortality rate. Univariate analysis utilizing the ANC difference compared to the admission day as the dependent variable, revealed no predictability role in the first three days of follow up for any of the variables included. However, during the fourth day of follow up, both WBC (OR = 0.261; 95% CI: 0.075, 0.908; p = 0.035) and lymphocyte percentage (OR = 1.074; 95% CI: 1.012, 1.141; p = 0.019) were marginally significant, in which increasing WBC was associated with a reduction in the likelihood of ANC count increase, compared to the lymphocyte percentage which exhibited an increase in the likelihood. In comparison, sequential ANC difference models demonstrated lymphocyte percentage (OR = 0.961; 95% CI: 0.932, 0.991; p = 0.011) and monocyte-to-lymphocyte ratio (OR = 7.436; 95% CI: 1.024, 54.020; p = 0.047) reduction and increment in the enhancement of ANC levels, respectively. The fifth day had WBC (OR = 0.790; 95% CI: 0.675, 0.925; p = 0.003) to be significantly decreasing the likelihood of ANC increment. Conclusions: we were unable to determine any concrete prognostic role of lymphocyte-related measures and ratios. It is plausible that several limitations could have influenced the results obtained, but as far as our analysis is concerned ALC role as a predictive factor for ANC changes remains questionable