Local Control Following Stereotactic Body Radiation Therapy for Liver Oligometastases: Lessons from a Quarter Century

The utilization of stereotactic body radiation therapy for the treatment of liver metastasis has been widely studied and has demonstrated favorable local control outcomes. However, several predictive factors play a crucial role in the efficacy of stereotactic body radiation therapy, such as the number and size (volume) of metastatic liver lesions, the primary tumor site (histology), molecular biomarkers (e.g., KRAS and TP53 mutation), the use of systemic therapy prior to SBRT, the radiation dose, and the use of advanced technology and organ motion management during SBRT. These prognostic factors need to be considered when clinical trials are designed to evaluate the efficacy of SBRT for liver metastases

Cytotoxic and HIV-1 enzyme inhibitory activities of Red Sea marine organisms

BACKGROUND: Cancer and HIV/AIDS are two of the greatest public health and humanitarian challenges facing the world today. Infection with HIV not only weakens the immune system leading to AIDS and increasing the risk of opportunistic infections, but also increases the risk of several types of cancer. The enormous biodiversity of marine habitats is mirrored by the molecular diversity of secondary metabolites found in marine animals, plants and microbes which is why this work was designed to assess the anti-HIV and cytotoxic activities of some marine organisms of the Red Sea. METHODS: The lipophilic fractions of methanolic extracts of thirteen marine organisms collected from the Red Sea (Egypt) were screened for cytotoxicity against two human cancer cell lines; leukaemia (U937) and cervical cancer (HeLa) cells. African green monkey kidney cells (Vero) were used as normal non-malignant control cells. The extracts were also tested for their inhibitory activity against HIV-1 enzymes, reverse transcriptase (RT) and protease (PR). RESULTS: Cytotoxicity results showed strong activity of the Cnidarian Litophyton arboreum against U-937 (IC50; 6.5 μg/ml ±2.3) with a selectivity index (SI) of 6.45, while the Cnidarian Sarcophyton trochliophorum showed strong activity against HeLa cells (IC50; 5.2 μg/ml ±1.2) with an SI of 2.09. Other species showed moderate to weak cytotoxicity against both cell lines. Two extracts showed potent inhibitory activity against HIV-1 protease; these were the Cnidarian jelly fish Cassiopia andromeda (IC50; 0.84 μg/ml ±0.05) and the red algae Galaxura filamentosa (2.6 μg/ml ±1.29). It is interesting to note that the most active extracts against HIV-1 PR, C. andromeda and G. filamentosa showed no cytotoxicity in the three cell lines at the highest concentration tested (100 μg/ml). CONCLUSION: The strong cytotoxicity of the soft corals L. arboreum and S. trochliophorum as well as the anti-PR activity of the jelly fish C. andromeda and the red algae G. filamentosa suggests the medicinal potential of crude extracts of these marine organisms.The Medical Research Council, the Technology Innovation Agency and the University of Pretoria, South Africa.http://www.biomedcentral.com/bmccomplementalternmedam201

Evaluation of circulating insulin-like growth factor-1, heart-type fatty acid-binding protein, and endotrophin levels as prognostic markers of COVID-19 infection severity

Abstract Background Coronavirus Disease 2019 (COVID-19) is a worldwide pandemic challenge spreading enormously within a few months. COVID-19 is characterized by the over-activation of the immune system causing cytokine storm. Insulin-like growth factor-1 (IGF-1) pathway can regulate the immune response via interaction with various implicated cytokines. Heart-type fatty acid-binding protein (H-FABP) has been shown to promote inflammation. Given the fact that coronavirus infections induce cytokines secretion leading to inflammatory lung injury, it has been suggested that H-FABP levels are affected by COVID-19 severity. Moreover, endotrophin (ETP), the cleavage product of collagen VI, may be an indicator of an overactive repair process and fibrosis, considering that viral infection may predispose or exacerbate existing respiratory conditions, including pulmonary fibrosis. This study aims to assess the prognostic capacity of circulating IGF-1, HFABP, and ETP, levels for COVID-19 severity progression in Egyptian patients. Methods The study cohort included 107 viral RNA-positive patients and an equivalent number of control individuals with no clinical signs of infection. Clinical assessments included profiling of CBC; serum iron; liver and kidney functions; inflammatory markers. Circulating levels of IGF-1; H-FABP, and ETP were estimated using the corresponding ELISA kits. Results No statistical difference in the body mass index was detected between the healthy and control groups, while the mean age of infected patients was significantly higher (P = 0.0162) than the control. Patients generally showed elevated levels of inflammatory markers including CRP and ESR concomitant with elevated serum ferritin; D dimer and procalcitonin levels, besides the COVID-19 characteristic lymphopenia and hypoxemia were also frequent. Logistic regression analysis revealed that oxygen saturation; serum IGF-1, and H-FABP can significantly predict the infection progression (P < 0.001 each). Both serum IGF-1 and H-FABP as well as O2 saturation showed remarkable prognostic potentials in terms of large AUC values, high sensitivity/specificity values, and wide confidence interval. The calculated threshold for severity prognosis was 25.5 ng/mL; 19.5 ng/mL, 94.5, % and for IGF-1, H-FABP, and O2 saturation; respectively. The calculated thresholds of serum IGF-1; H-FABP, and O2 saturation showed positive and negative value ranges of 79–91% and 72–97%; respectively, with 66–95%, 83–94% sensitivity, and specificity; respectively. Conclusion The calculated cut-off values of serum IGF-1 and H-FABP represent a promising non-invasive prognostic tool that would facilitate the risk stratification in COVID-19 patients, and control the morbidity/mortality associated with progressive infection

Chetomin, a SARS-CoV-2 3C-like Protease (3CL^pro) Inhibitor: <i>In Silico</i> Screening, Enzyme Docking, Molecular Dynamics and Pharmacokinetics Analysis

The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues –namely, chetomin A-D– as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate

An unusual 2-<i>O</i>-glyceryl-glycosyl-γ-pyrone from <i>Erigeron annuus</i> (L.) with potential antifungal activity: <i>in-vitro</i> and <i>in-silico</i> study

Phytochemical characterisation of the polar fraction of Erigeron annuus extract led to the isolation of glycerylerigeroside (1), a unique γ-pyrone derivative. Structure of 1 was decided by intensive study of NMR and mass spectra as 3-O-[4'-((1,3-dihydroxypropan-2-yl)oxy)-β-D-glucopyranoside)]-4H-pyran-4-one, with uncommon glyceroxy side chain attached to 4’ position of pyromeconic acid β-D-glucopyranoside. Antimicrobial potential of 1 was tested against Staphylococcus aureus, Salmonella enterica, and Candida albicans. Compound 1 strongly inhibited growth of Candida albicans (MIC = 17.24 µM/disc), compared to fluconazole (MIC = 16.33 µM/disc). Meanwhile, it moderately inhibited the growth of Staphylococcus aureus (MIC = 71.84 µM/disc) and Salmonella enterica (MIC = 71.84 µM/disc), as compared with thiophenicol (MIC = 14.05 µM/disc) and (MIC = 14.05 µM/disc), respectively. The binding mode of 1 with the active site of sterol 14α-demethylase (CYP51) from Candida albicans (PDB ID: 5TZ1), in combination with fluconazole, was predicted by molecular docking study and supported the antifungal activity.</p

Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins&mdash;namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)&mdash;demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of &minus;58.9, &minus;55.9, &minus;50.1, and &minus;43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin&mdash;a venom of the Egyptian solitary wasp&mdash;holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation

Paralemnolins X and Y, New Antimicrobial Sesquiterpenoids from the Soft Coral Paralemnalia thyrsoide

The organic extracts of the Red Sea soft coral Paralemnalia thyrsoides has led to the identification of two neolemnane-type sesquiterpenoids: paralemnolins X and Y (1, 2). In addition to these newly characterized compounds, ten known metabolites (3–12) were isolated. Previously reported compounds were elucidated by literature comparison of spectroscopic data (1D and 2D NMR as well as MS data). In vitro antimicrobial activity was investigated for compounds (1–12) against Staphylococcus aureus, Escherichia coli, Candida albicans and Aspergillus niger. Compound 5 showed antimicrobial activity against all assayed microorganisms