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Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Background Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett’s multiple comparison test. Results We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration ( n  ≥ 3, p  < 0.05) and invasion ( n  ≥ 3, p  < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model ( p  < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content ( n  ≥ 3, p  < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 ( p  < 0.05) or 21 days ( p  < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

Bee venom (BV) is a rich source of secondary metabolites from honeybees (Apis mellifera L.). It contains a variety of bioactive ingredients including peptides, proteins, enzymes, and volatile metabolites. The compounds contribute to the venom’s observed biological functions as per its anti-inflammatory and anticancer effects. The antimicrobial action of BV has been shown in vitro and in vivo experiments against bacteria, viruses, and fungi. The synergistic therapeutic interactions of BV with antibiotics has been reported. The synergistic effect contributes to a decrease in the loading and maintenance dosage, a decrease in the side effects of chemotherapy, and a decrease in drug resistance. To our knowledge, there have been no reviews on the impact of BV and its antimicrobial constituents thus far. The purpose of this review is to address the antimicrobial properties of BV and its compounds.

A robust, stability-indicating, and eco-friendly proton nuclear magnetic resonance ( 1 H-qNMR) method was developed for the concurrent determination of three 1,4-benzodiazepines (BDZs), namely diazepam (DZP), alprazolam (ALP), and chlordiazepoxide (CDP) and their common impurity, synthesis precursor, and degradation product; 2-amino-5-chlorobenzophenone (ACB). In the present method, a novel approach was developed for composing a green and cost-efficient solvent system as an alternative to the common NMR organic solvents utilizing 0.3 M sodium dodecyl sulfate prepared in deuterated water. The conducted method is characterized by simplicity with no need for sample pretreatment or labeling. Phloroglucinol was used as an internal standard. The chosen signals for the determinations of ALP, CDP, DZP and ACB were at 2.35 ppm (singlet), 2.84 ppm (singlet), 3.11 ppm (singlet), and 6.90 ppm (doublet of doublet), respectively. The proposed method possessed linearity over the concentration range of 0.25–15.0 mg ml −1 for DZP, ALP, CDP and of 0.5–25.0 mg ml −1 for ACB with LOD values of 0.06, 0.03, 0.07 and 0.16 mg ml −1 respectively, and LOQ values of 0.18, 0.09, 0.21 and 0.49 mg ml −1 , respectively. Accuracy of the method was evidenced by excellent recovery% (99.57–99.90%) and small standard deviation (≥ 1.10) for the three analyzed drugs. Intra- and inter-day precision were determined with coefficient of variation ranging from 0.12 to 1.14 and from 0.72 to 1.67, respectively. For the studied compounds, appraisal of the method greenness was achieved via four approaches: Analytical Eco-Scale, Green Analytical Procedure Index (GAPI), Analytical greenness metric (AGREE), and RGB Additive Color Model. The results proved that the proposed method has the privilege of being a green analytical method.

Pantoprazole has an antioxidant function against reactive oxygen species (ROS). Vincamine, a herbal candidate, is an indole alkaloid of clinical use against brain sclerosis. The aim of the present experiment is to evaluate, on a molecular level for the first time, the value of vincamine in addition to pantoprazole in treating experimentally induced renal ischemia/reperfusion injury (IRI). One-hundred-and-twenty-eight healthy male Wistar albino rats were included. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were assessed. ELISA was used to estimate the pro-inflammatory cytokines. The expression of Bcl-2 and Bax genes was assessed by quantitative real-time PCR. ERK1/2, JNK1/2, p38, cleaved caspase-3, and NF-κB proteins expressions were estimated using western blot assay. The kidneys were also histopathologically studied. The IRI resulted in impaired cellular functions with increased creatinine, urea nitrogen, malondialdehyde, TNF-α, IL-6, and IL-1β serum levels, and up-regulated NF-ĸB, JNK1/2, ERK1/2, p38, and cleaved caspase-3 proteins. Furthermore, it down-regulated the expression of the Bcl-2 gene and upregulated the Bax gene. The treatment with vincamine, in addition to pantoprazole multiple doses, significantly alleviated the biochemical and histopathological changes more than pantoprazole or vincamine alone, whether the dose is single or multiple, declaring their synergistic effect. In conclusion, vincamine with pantoprazole multiple doses mitigated the renal IRI through the inhibition of apoptosis, attenuation of the extracellular signaling pathways through proinflammatory cytokines’ levels, and suppression of the MAPK (ERK1/2, JNK, p38)–NF-κB intracellular signaling pathway.

Propolis, a resin produced by honeybees, has long been used as a dietary supplement and folk remedy, and more recent preclinical investigations have demonstrated a large spectrum of potential therapeutic bioactivities, including antioxidant, antibacterial, anti-inflammatory, neuroprotective, immunomodulatory, anticancer, and antiviral properties. As an antiviral agent, propolis and various constituents have shown promising preclinical efficacy against adenoviruses, influenza viruses, respiratory tract viruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 300 chemical components have been identified in propolis, including terpenes, flavonoids, and phenolic acids, with the specific constituent profile varying widely according to geographic origin and regional flora. Propolis and its constituents have demonstrated potential efficacy against SARS-CoV-2 by modulating multiple pathogenic and antiviral pathways. Molecular docking studies have demonstrated high binding affinities of propolis derivatives to multiple SARS-CoV-2 proteins, including 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), the receptor-binding domain (RBD) of the spike protein (S-protein), and helicase (NSP13), as well as to the viral target angiotensin-converting enzyme 2 (ACE2). Among these compounds, retusapurpurin A has shown high affinity to 3CLpro (ΔG = −9.4 kcal/mol), RdRp (−7.5), RBD (−7.2), NSP13 (−9.4), and ACE2 (−10.4) and potent inhibition of viral entry by forming hydrogen bonds with amino acid residues within viral and human target proteins. In addition, propolis-derived baccharin demonstrated even higher binding affinity towards PLpro (−8.2 kcal/mol). Measures of drug-likeness parameters, including metabolism, distribution, absorption, excretion, and toxicity (ADMET) characteristics, also support the potential of propolis as an effective agent to combat COVID-19.

Introduction: In Egypt, there is a paucity of new data regarding awareness of HIV/AIDS among physicians. This study aimed to assess the level of awareness, attitude, practice, and knowledge of a sample of Egyptian physicians regarding HIV regarding natural history, epidemiology, and virology, method of transmission, clinical manifestations, diagnosis, prevention, and management. Methodology: Sixty-eight Egyptian physicians were enrolled in an observational analytic multicenter cross-sectional KAP study in Egyptian tertiary health care facilities covering different localities, including New Valley University, Assiut University, South Valley University, Helwan University, Alexandria University, Aswan University, and Al-Azhar University. Results: The attitude of physicians towards the privacy of persons living with HIV, was the one with the highest percentage 85.3%. On the other hand, respondents think that only 25% of physicians do not stigmatize HIV patients. Moreover, only 25% of the study group do not stigmatize persons living with HIV. The highest proportion of favorable practice was 39.7% and the lowest was 17.6%. With regard to their knowledge about HIV, the lowest proportion of correct answers to a question was 4.4%, and the highest proportion was 92.6%. Most of the enrolled physicians were found to have a moderate knowledge score, 49/68 (72%). There was a significant difference between different specialties regarding knowledge scores. Conclusions: There are some knowledge gaps among a sample of Egyptian physicians with regard to HIV/AIDS. In addition, Egyptian physicians may have a moderate degree of undesirable attitude and practice toward HIV/AIDS.

Background There are no studies investigating the role of midkine (MK) in vascular calcification (VC) or vascular disease associated with chronic kidney disease (CKD). This study assessed serum MK level and investigated its relationship with carotid atherosclerosis and coronary artery calcification (CAC) in non-dialysis CKD. Methods The study comprised 80 controls and 185 adult patients with CKD at stages 3–5 who were free of cardiovascular diseases. Acute renal failure, chronic hemodialysis, severe liver disease, inflammatory states, anticoagulation therapy and cancer were excluded. The patients were classified based on presence of CAC score into severe and mild to moderate CAC groups. They were also divided into atherosclerotic and non-atherosclerotic groups based on carotid atherosclerosis. CBC, kidney function tests, lipid profile, intact parathyroid hormone (iPTH), and phosphorus were assessed. Serum levels of MK, tumor necrosis factor- α (TNF- α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were quantitatively tested using ELISA. Cardiac CT scan was done to calculate CAC score. Carotid ultrasonography was used to evaluate carotid intima media thickness (CIMT) and identify plaques. Results All CKD categories, including CKD-3, CKD-4, and CKD-5, showed higher rates of carotid plaques ( p  = 0.007, p  < 0.001, and p  < 0.001, respectively), higher levels of MK ( p  < 0.001 for each), and higher CAC scores ( p  < 0.001 for each) as CKD worsened. Compared to mild to moderate CAC patients, severe CAC patients showed increased CIMT ( p  < 0.001) and raised serum levels of MK ( p  < 0.001), TNF-α ( p  = 0.001), IL-6 ( p  = 0.002), hs-CRP ( p  = 0.003), iPTH ( p  = 0.02), phosphorus ( p  < 0.001), total cholesterol (TC), and low density lipoprotein-cholesterol (LDL-C). Multivariate linear regression revealed that CAC was reliably predicted by MK ( p  = 0.008) and serum creatinine ( p  = 0.001). Carotid atherosclerotic patients had higher serum levels of MK, TNF-α, IL-6, hs-CRP, iPTH, phosphorus, TC, total triglycerides and LDL-C ( p  < 0.001 for each). Multivariate logistic regression showed that serum MK ( p  = 0.001), serum creatinine ( p  = 0.005), age ( p  < 0.001), iPTH ( p  = 0.007), and IL-6 ( p  = 0.024) were significant predictors of carotid atherosclerosis. Conclusions As CKD worsened, MK levels, carotid atherosclerosis and CAC increased. Serum MK was a reliable biomarker for asymptomatic carotid atherosclerosis and CAC in non-dialysis CKD, allowing prompt early diagnosis to avert cardiovascular morbidity and death in the future. Trial registration The trial number was 1138 and its registration was approved by the hospital’s Research Ethics Committee in 4/2024.

We studied the characteristics and survival of patients with sorafenib-treated HCC and impact of underlying etiology on outcomes. This retrospective multicenter study recruited patients with sorafenib-treated advanced HCC (12/2016 to 4/2023) till death or the study end (2/2024). Time to progression (TTP) and overall survival (OS) were recorded. We evaluated; Clinico-laboratory and imaging predictors of OS, The impact of underlying etiology on tumor variables, outcomes and tolerance for sorafenib > 6 months. This study included 706 patients. Median duration of Sorafenib therapy was 240.00 (90.00–360.00) days. Median OS was 314.00(146.00–601.00) days. Median TTP was 180.00(90.00–330.00) days. COX regression revealed that the independent factors of mortality were baseline AST, Tumor size, hepatic vein thrombosis (HVT), development of jaundice and shifting to Regorafenib. Advanced HCCs were more common on top of non-cirrhotic non-viral and HBV-related liver disease. Adverse events, TTP and tumor response didn’t differ with the underlying etiology. Median OS was lower in non-viral-related HCC than HCV-related HCC (218.00 versus 326.50 days, P -value = 0.048). Patients who continued sorafenib > 6 months had lower AFP, HVT, adverse effects and better tumor response after 3 months. OS is lower in non-viral Sorafenib-treated HCC compared with viral-related HCC and Sorafenib was well-tolerated among different HCC etiologies.

A pipelined framework is proposed for accurate, automated, simultaneous segmentation of the liver as well as the hepatic tumors from computed tomography (CT) images. The introduced framework composed of three pipelined levels. First, two different transfers deep convolutional neural networks (CNN) are applied to get high-level compact features of CT images. Second, a pixel-wise classifier is used to obtain two output-classified maps for each CNN model. Finally, a fusion neural network (FNN) is used to integrate the two maps. Experimentations performed on the MICCAI’2017 database of the liver tumor segmentation (LITS) challenge, result in a dice similarity coefficient (DSC) of 93.5% for the segmentation of the liver and of 74.40% for the segmentation of the lesion, using a 5-fold cross-validation scheme. Comparative results with the state-of-the-art techniques on the same data show the competing performance of the proposed framework for simultaneous liver and tumor segmentation.