•One-third of pediatric tumor patients require radiotherapy.•High pediatric radiotherapy utilization rate in a middle-income country.•Pediatric soft tissue sarcoma requires the highest radiotherapy ...utilization rate.•Palliative radiotherapy is frequently used for brainstem glioma patients.•Palliative radiotherapy is underutilized in childhood cancers.
Although the radiotherapy utilization rate (RUR) is determined for most adult cancers, it is seldom reported in childhood tumors, particularly in low- and middle-income countries (LMIC) where the majority of pediatric cancer patients reside. This study aims to investigate the real-life RUR for pediatric tumors in a large LMIC center.
The electronic files of patients treated at a single institution during 2010–2017 were reviewed and the RUR was defined as the percentage of patients who received at least one radiotherapy (RT) course from the total number of patients.
A total of 4390 out of 13,305 pediatric cancer patients received at least one RT course with a RUR of 33%. The curative, salvage, and palliative RURs were 27.8%, 2%, and 5.7%, respectively. There was a considerable variation in the RUR between various tumors, ranging from 0% in choroid plexus papilloma and other rare tumors to 100% in intracranial germinoma. Moreover, the RUR varied among different stages within each tumor type. Overall, 753 patients received 920 palliative RT courses (range 1–9) at a median dose of 30 Gy. The most commonly irradiated metastatic sites were the bone (34%) and the brain (9.8%).
This is the first analysis to provide valuable insights into the RUR for childhood tumors. Together with population-based pediatric cancer registries, this will help decipher pediatric RT needs and deficits. Additionally, the underutilization of palliative RT calls for multidisciplinary palliative care provision for pediatric cancer patients.
•T-1-MMPA was designed according to the essential pharmacophoric characteristics EGFR inhibitors.•T-1-MMPA potential to inhibit EGFR was indicated by DFT, Docking, MD, MM-GPSA, PLIP, ED, and ...ADMET.•In vitro studies showed that T-1-MMPA was effective against MDA-MB-231 and other three cancer cell lines.•T-1-MMPA prevented MDA-MB-231 haling, arrested its growth at the s phase, induced apoptosis, and decreased BCL2 and MMP7 gene expression.•T-1-MMPA’s hepatic safety was further corroborated through in vivo investigation.
A new EGFR inhibitor has been developed from theobromine (meta methoxy phenyl)acetamide derivative), T-1-MMPA, exhibited the essential pharmacophoric characteristics needed to bind toEGFR's pocket. T-1-MMPA's anticancer potential was first estimated through various structure-based computational studies (DFT, docking, MD simulations over 200 ns, MM-GPSA, PLIP, ED, bi-dimensional and ADMET), which revealed that T-1-MMPA effectively bound to and inhibited the EGFR protein. The ADME and toxicity profiles of T-1-MMPA were also predicted computationally before the semi synthesis, and a high degree of drug-likeness was indicated. Then, T-1-MMPA (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(3-methoxyphenyl)acetamide) was prepared to scrutinize the obtained in silico results. Subsequent in vitro studies showed that T-1-MMPA was effective against MDA-MB-231cell lines (triple-negative breast cancer), with an IC50 value of 1.42 µM, compared to the reference drug (0.92 µM) and exhibited a higher selectivity index of 1.9. Interestingly, T-1-MMPA also inhibited the growth of other three cancer cell lines (A549, CaCO-2, and HepG-2) with IC50 values of 1.57, 1.76, and 2.53 µM, respectively. Additionally, T-1-MMPA effectively prevented the healing and migration abilities of the MDA-MB-231 cell lines, arrested the cell growth at the S phase and induced apoptosis, as confirmed by AO/EB staining assay as well as the flow cytometry. Moreover, T-1-MMPA caused down-regulation of the BCL2 and MMP7 gene expression in the treated MDA-MB-231 cells. Finally, as the computational findings indicated T-1-MMPA’s hepatic safety, it was further corroborated through in vivo investigation.
A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is ...a (para-chloro)acetamide derivative of the alkaloid, theobromine, (
). At first, we started with deep density functional theory (DFT) calculations for
to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for
. Secondly, the affinity of
to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR
and EGFR
, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of
have been investigated and its safety and the general drug-likeness predicted. Accordingly,
was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly,
inhibited in vitro EGFR
with an IC
value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally,
inhibited the growth of A549 and HCT-116 malignant cell lines with IC
values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC
values of 6.73 and 16.35 µM, respectively.
A computer-assisted drug design (CADD) approach was utilized to design a new acetamido-N-(para-fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T-1-APFPB), ...following the pharmacophoric features of VEGFR-2 inhibitors. The stability and reactivity of T-1-AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T-1-AFPB's potential to bind with and inhibit VEGFR-2. The precise binding of T-1-AFPB against VEGFR-2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM-GBSA, and PCA studies. Then, T-1-AFPB (4-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamido)-N-(4-fluorophenyl)benzamide) was semi-synthesized and the in vitro assays showed its potential to inhibit VEGFR-2 with an IC
value of 69 nM (sorafenib's IC
was 56 nM) and to inhibit the growth of HepG2 and MCF-7 cancer cell lines with IC
values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T-1-AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T-1-AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T-1-APFPB providing it as a promising lead VEGFR-2 inhibitor for further development aiming at cancer therapy.
To evaluate the corneal pachymetric and topographic parameters of systemic Lupus Erythematosus (SLE) patients using Dual Scheimpflug Imaging.
This observational cross-sectional controlled study ...included the right eye of 30 SLE patients and 30 age-matched controls. Corneal measurements were acquired by dual Scheimpflug imaging including anterior and posterior corneal curvatures, central, mid-peripheral corneal thickness (measured at the 5 mm zone) and peripheral pachymetry (measured at the 7 mm zone). SLE disease activity index (SLEDAI) was calculated and correlated with corneal pachymetry.
SLE patients had significantly thicker corneal periphery than controls. Mean central corneal pachymetry was 530.4± 27.3 microns (SD) in SLE and 547.5±31.5 microns (SD) in control group, p = 0.032. The corneal periphery - except superiorly - was significantly thicker in SLE patients than controls (p ˂0.001). Nasal peripheral corneal thickness positively correlated with disease activity index SLEDAI (p=0.03).
SLE patients present with thicker corneal periphery than controls characteristically sparing the superior quadrant. Possible corneal photosensitivity leading to peripheral immune complex deposition as well as flatter posterior corneal surface at the periphery are proposed explanations for these findings.
Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of ...existing EGFR inhibitors as a foundation. Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative (T-1-PMPA). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA. Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA’s binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA. Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations. Results: DFT studies indicated T-1-PMPA’s reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA’s safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFRWT and EGFR790m, with IC50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA. Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib’s values (84 and 74%), respectively. Conclusion: In conclusion, our study’s findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR.
VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine ...analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA’s oral treatment didn’t show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.
Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors.
antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 cancer cell lines. The top ...cytotoxic members
,
,
, and
were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate
, these studies revealed the ability of compound
to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late apoptosis. Also compound
was found to significantly decrease the levels immunomodulatory proteins TNF-α and IL-6 while showing a four-fold rise in an apoptotic marker caspase-3 when compared to control cells. The therapeutic index of the designed derivatives was evaluated by computational ADMET and toxicity calculations as well as their potentiality to occupy the VEGFR-2 active site was signposted by molecular docking assessments. Finally, molecular dynamic simulation studies of compound
-VEGFR-2 complex indicated the high steadiness of compound
in the VEGFR-2 active site. This study presents compound
as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.
Our aim was to review and externally validate all the available predictive tools (PTs) predicting extraprostatic extension (EPE) using the area under the curve, calibration plots, and scaled Brier ...score.
A literature search was performed showing 19 models predicting EPE. External validation was carried out on 6360 prostate cancer patients submitted to RP. Most of the PTs showed poor discrimination and unsatisfactory calibration.
The majority of the available PTs are not reliable for the prediction of EPE in populations other than the development one; thus, they may not be completely appropriate for patients’ counselling or for surgical strategy preplanning.
In the food and fertilizer industries, zinc oxide nanoparticles (ZnO-NPs) are frequently utilized. Our study conducted to assess the genotoxicity, biochemical alterations and histopathological ...parameters of ZnO NPs with a particle size of 30 ± 5 nm were orally administered to rats once daily at doses of 100, 200, 300, 400, and 600 mg/kg for ten week. The experiment involved the use of 30 Sprague–Dawley male rats exposed to various concentrations of ZnO-NPs. After the adaptation period, six groups were created out of the thirty rats (Five rats per group). Rats in Group 1 (G1), known as the control group, were fed a standard synthetic meal and had unlimited access to drinking water ad libitum, while those in the other five groups received oral gavage treatments with various doses of zinc oxide nanoparticles over a 10-week period. The results indicated that ZnO-NPs induces a lowering in body weight beginning in the sixth week while increasing serum AST, ALT, creatinine, and uric acid activity. However, the addition of different concentrations of ZnO NPs compared to the control caused insignificantly decreased on the plasma glucose level in all treated animals. Numerous chromosomal aberrations, including fragments, chromosome rings, chromatid breaks, end-to-end association, and centric fusion, were observed through cytogenetic investigation. When compared to the control group, hepatic vacuolation, large sinusoidal dilatation, degenerative alterations, and cellular congestion were observed in the liver of the male rats treated with 400 and 600 mg/kg of ZnO-NPs. According to the findings of in vivo genotoxicity experiments, rats' bone marrow cells, liver, and kidney can exhibit genotoxicity and cytotoxicity after exposed to ZnO NPs with particle sizes of 30 nm for ten weeks. The findings of this study could raise more concerns regarding the potential damage to human health associated with the widespread use of ZnO NPs.
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