An overview of RAF kinases and their inhibitors (2019-2023).

Protein kinases (PKs) including RAF, perform a principal role in regulating countless cellular events such as cell growth, differentiation, and angiogenesis. Overexpression and mutation of RAF kinases are significant contributors to the development and spread of cancer. Therefore, RAF kinase inhibitors show promising outcomes as anti-cancer small molecules by suppressing the expression of RAF protein, blocking RAS/RAF interaction, or inhibiting RAF enzymes. Currently, there are insufficient reports about approving drugs with minimal degree of toxicity. Therefore, it is an urgent need to develop new RAF kinase inhibitors correlated with increased anticancer activity and lower cytotoxicity. This review outlines reported RAF kinase inhibitors for cancer treatment in patents and literature from 2019 to 2023. It highlights the available inhibitors by shedding light on their chemical structures, biochemical profiles, and current status. Additionally, we highlighted the hinge region-binding moiety of the reported compounds by showing the hydrogen bond patterns of representative inhibitors with the hinge region for each class. In recent years, RAF kinase inhibitors have gained considerable attention in cancer research and drug development due to their potential to be studied under clinical trials and their demonstration of various degrees of efficacy and safety profiles across different cancer types. However, addressing challenges related to drug resistance and safety represents a major avenue for the optimization and enhancement of RAF kinase inhibitors. Strategies to overcome such obstacles were discussed such as developing novel pan-RAF inhibitors, RAF dimer inhibitors, and combination treatments.

An overview of the latest outlook of sulfamate derivatives as anticancer candidates (2020-2024).

Considering the emergence of new anticancer drugs, in this review we emphasized and highlighted the recent reports and advances related to sulfamate-incorporating compounds with potential anticancer activity during the last 5 years (2020-2024). Additionally, we discussed their structure-activity relationship, clarifying their potent bioactivity as anticancer agents. Sulfamate derivatives hold promise as effective therapeutic candidates against cancer. By targeting biological targets associated with the development of cancer, such as steroid sulfatases (STS), carbonic anhydrases (CAs), microtubules, NEDD8-activating enzyme, small ubiquitin-like modifiers (SUMO)-activating enzyme (SAE), cyclin-dependent kinases (CDKs), breast cancer susceptibility gene 1 (BRCA1), and so on, this can furnish small molecules as anticancer lead candidates serving the drug discovery field. For example, compound 2, an STS inhibitor, demonstrated superior activity compared to its reference, irosustat, by fivefold. In addition, compound 21, an SAE, is under phase I clinical trials. Continued research into sulfamate derivatives holds potential for the development of novel therapeutic agents targeting various diseases.

Design and discovery of urease and Helicobacter pylori inhibitors based on benzofuran/benzothiophene-sulfonate and sulfamate scaffolds for the treatment of ureolytic bacterial infections.

A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC50 value of 0.42 ± 0.08 µM, which is 53-fold more potent than thiourea, positive control (IC50 = 22.3 ± 0.031 µM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.

Changes in the Parameters of Visual Evoked Potentials in Media Opacities.

Purpose: This study compared flash visual evoked potentials (VEPs) parameter differences between eyes with unilateral opaque media and their normal contralateral counterparts. Patients and Methods: We included 178 patients with unilateral media opacity and normal contralateral eye in each patient. The diseased eyes had normal ultrasonographic findings and were candidates for keratoplasty or anterior segment reconstruction. The patients underwent electrophysiological testing by the flash VEPs recording with the use of 1.4Hz (transient) and 8Hz (flicker) frequencies. Results: The medians of P2 implicit times were significantly higher in eyes with media opacity than in normal eyes, with median differences between both eyes of -6.7 ms. Furthermore, the median N2P2 amplitude was 9.70 µv with media opacity compared with 11.00 µv in the normal eyes, with a significant difference of 1.3 (p = 0.002). The flash VEPs median parameters recorded at a frequency of 8-Hz showed significant differences in medians of spectral plots of 0.6 µv between normal and abnormal eyes. The same for the signal-to-noise ratio, where the difference in medians was 3 dB. Analysis of the difference between both eyes (normal-abnormal) in each patient showed in P2 implicit time a difference range of -49 to 54.7 ms with a median difference of -3 ms. The difference in amplitudes of recorded N2P2 showed a median of 2.13 µv. There was a statistically significant but weak negative correlation between N2P2 amplitude (r spearman = -0.173, p = 0.021) and the grades of corneal opacity. Conclusion: Preoperative flash VEPs recording is useful for evaluating visual function in patients with unilateral media opacity to determine the future benefits of keratoplasty or anterior segment reconstruction. There are no correlations between the flash VEP parameters or the difference between the 2 eyes and the grades of corneal opacity.

Ten-Year Outcomes of LASIK for Pediatric Myopic Anisometropia.

Purpose: To evaluate long-term safety, effectiveness, and stability of unilateral LASIK in pediatric myopic anisometropic amblyopia. Methods: This retrospective study included children who received unilateral LASIK for myopic anisometropia of >6 D, after mandatory 6-month occlusion/penalization therapy. They were evaluated at 6 months, 1 year, 2 years and biannually until 10 years. Outcome measures included visual acuity, refraction, ocular alignment, stereopsis, corneal clarity, and corneal topography. Results: 32 patients (16 girls) with mean age of 8.6 ± 2.3 years completed 10 years of follow up after unilateral LASIK. Mean preoperative spherical equivalent refraction (SER) was -10.3D ±2.0D in the affected eye, with anisometropic difference of -9.5D ±1.7D. Mean post-LASIK SER was -1.3D±0.8D (p<0.001). Anisometropia significantly decreased to 0.3D±0.8D, 0.4D±1.0D, and 1.0±2.5D at 6 months, 1 year and 10 years respectively (p<0.001). 11 patients (34%) who had preoperative intermittent exotropia (< 15°) regained orthophoria in all gazes, while 5 of 10 who had constant exotropia with large angle (>30°) required strabismus surgery for ocular alignment. BCVA improved from 0.04±0.6 Decimal at baseline to 0.6 ±0.2 after LASIK and occlusion therapy (p< 0.001). Despite insignificant refractive regression in both eyes, patients have maintained orthophoria, improved stereopsis, clear cornea, and the topography showed no evidence of post-LASIK ectasia. Conclusion: LASIK appears safe, effective, and stable for correcting refractory pediatric myopic anisometropia, in which conventional measures fail or endanger normal visual development. Eliminating anisometropic aniseikonia consequently restores binocular vision and stereopsis which, along with amblyopia therapy, would reverse amblyopia and prevent recurrence.

Synthesis of a new magnetic Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base for Cr(VI) removal.

In this study, a novel magnetic organic-inorganic composite was fabricated. Chitosan, sulfacetamide and ethylacetoacetae were used to prepare a new Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base (SEH-CSB) with a variety of active sites that capable of forming coordinate covalent bonds with Cr(VI). This was followed by modification of the formed SHE-CSB with NiFe2O4 to obtain the magnetic Chitosan-Schiff-base composite (NiFe2O4@SEH-CSB). NiFe2O4@SEH-CSB was characterized using FTIR, zeta potential, SEM, VSM and XPS. Results clarified that SHE played a crucial role in the removal of Cr(VI). The removal of Cr(VI) on NiFe2O4@SEH-CSB was found to be more fitted to pseudo-second order kinetics model and Freundlich isotherm. Besides, the maximum adsorption capacity of NiFe2O4@SEH-CSB towards Cr(VI) was found to be 373.61 mg/g. The plausible mechanism for the removal of Cr(VI) by NiFe2O4@SEH-CSB composite suggested the domination of coulombic interaction, outer-sphere complexation, ion-exchange, surface complexation and coordinate-covalent bond pathways. The magnetic property enabled easy recycling of NiFe2O4@SEH-CSB composite for seven sequential cycles.

Treatment of Epithelial Basement Membrane Dystrophy to Optimize the Ocular Surface Prior to Cataract Surgery.

Purpose: To assess the effectiveness of cryopreserved amniotic membrane (CAM) after debridement in treating epithelial basement membrane dystrophy (EBMD) prior to cataract surgery. Methods: This pilot study included 2 treatment groups: a prospective study group of 9 subjects with significant EBMD who received debridement followed by self-retained CAM, and a retrospective, control group of 10 consecutive subjects who received debridement followed by a bandage contact lens (BCL). Slit-lamp photography after fluorescein staining were used to monitor healing. Corneal topography and IOL calculation were compared at baseline and 1 month after the procedure. Refraction and ocular surface stability were also compared after cataract surgery. Results: Corneal reepithelialization after debridement occurred in 4.6 ± 0.8 days in the study group and 6.8 ± 0.6 days in the control (p < 0.05). Corneal topography showed changes in curvature from 43.5 ± 1.2D at baseline to 44.6 ± 1.2D at 1 month in the study group and from 45.0 ± 0.6D to 45.7 ± 0.8D in the control (p = 0.38). Average change in IOL calculation was 1.56 D in the study group, compared to 0.95 D in control (p = 0.29). Post-cataract refraction in both groups was within ±0.5 Diopter of the anticipated, and corneal surface remained stable without EBMD recurrence. Conclusion: Management of ocular surface disorders prior to cataract surgery stabilizes IOL calculation and reduces postoperative refractive surprises. CAM relatively accelerated healing after debridement; however, it was not better than BCL in stabilizing the ocular surface and improving visual outcome. The use of CAM in cases of EBMD remains speculative.

Extra Ocular Muscle Fenestration as a Weakening Maneuver for Surgical Management of Strabismus: A Randomized Pilot Clinical Trial.

PURPOSE: This study aimed to evaluate the efficacy and safety of fenestration in comparison to the classic muscle recession as a weakening maneuver to horizontal and vertical extra ocular muscles in the surgical management of strabismus. PATIENTS AND METHODS: This is a pilot single blind parallel group randomized controlled trial with 1:1 allocation ratio. Male or female patients aged 1- to 60-years-old who were admitted to the Pediatric Ophthalmology and Strabismus Department for surgical correction of horizontal or vertical strabismus. Patients were randomly allocated by the envelop method to either group 1 (muscle fenestration, N=9) or group 2 (classic muscle recession, N=9). All participants were assessed at the first post operative day, at one week, and one month after the surgery for the outcomes. RESULTS: Postoperative ocular alignment evaluated at the first day, one week, and one month following the operation showed comparable results with no significant differences between both groups (p>0.05). The median postoperative pain score evaluated at the first day following the operation was significantly higher in fenestration group than recession group (the medians were 2.0 and 1.0, respectively, p=0.014). Alternatively, the medians of the pain score were equal in both groups at one week and one month postoperatively (p>0.999). One patient in the fenestration group developed progressive subconjunctival hemorrhage. In contrast, there was no postoperative complications in the recession group (p>0.999). CONCLUSION: Efficacy and safety of muscle fenestration for correcting horizontal or vertical strabismus was comparable to the classic muscle recession.

Intraocular Pressure Calculation in Myopic Patients After Laser-Assisted In Situ Keratomileusis.

BACKGROUND: Corneal refractive surgery is widely used worldwide. Myopia is the most common reason for laser-assisted corneal refractive surgery (LASIK) and one of the risk factors for glaucoma. Intraocular pressure (IOP) measurement becomes variable postoperatively as the results are affected by the decrease in corneal thickness and biomechanics. This prospective clinical case study attempted to establish a simple correction formula for the calculation of IOP in post-LASIK myopic patients. METHODS: This study included 300 eyes of 150 patients with myopia and myopic astigmatism as a refractive error who underwent LASIK. IOP was measured preoperatively and 6 months postoperatively. Preoperative and postoperative corneal thickness as well as ablation depth were measured. Statistical analysis was performed to detect the relationship between ablation depth and change in IOP. An attempt was made to construct a correction formula for the calculation of post-LASIK IOP. RESULTS: The age of the patients ranged between 18 and 50 (mean ± SD 34.78±8.8) years. The spherical equivalent of refractive error ranged between -1.5 and -10 diopters. The mean IOP decreased significantly from 15.72±2.37 mmHg preoperatively to 11.71±2.24 mmHg postoperatively, with a mean difference of 4±1.75 mmHg (p˂0.001). A positive correlation was detected between corneal thickness and IOP difference among patients both preoperatively and postoperatively (p˂0.001). A positive correlation was identified between ablation depth and IOP change (p˂0.001). The correction formula for IOP was established: Real IOP=4+0.7(preoperative IOP)-0.3(ablation depth). CONCLUSION: IOP measurements change after corneal refractive surgery with LASIK. A corrected formula may be a good option for the proper calculation of post-LASIK IOP.

Update On Cenegermin Eye Drops In The Treatment Of Neurotrophic Keratitis.

Neurotrophic keratitis is an underdiagnosed degenerative condition induced by impairment to the corneal nerves which may lead to persistent epithelial defects and corneal blindness. Current medical and surgical treatments are only supportive and poorly tackle the underlying problem of corneal anesthesia; hence, fail to provide a permanent cure. Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF) that may address this issue. Preliminary clinical trials have demonstrated the safety and efficacy of topical cenegermin in patients with moderate to severe neurotrophic keratitis; however, the clinical experience with this drug is still limited. This review summarizes the pathogenesis and management of neurotrophic keratitis as well as the mechanism of action, uses, and limitations of cenegermin eye drops in the treatment of neurotrophic keratitis.

New use of 8-0 polypropylene suture for four-point scleral fixation of secondary intraocular lenses.

We describe 4-point scleral fixation of a posterior chamber intraocular lens (PC IOL) using 8-0 polypropylene (Prolene) sutures, without the handshake technique. First, 4 sclerotomy sites are marked 2.5 mm from the limbus, and 2 scleral grooves are created in between. Two sets of 8-0 polypropylene sutures are then passed through the IOL haptics. The PC IOL is inserted behind the iris, and the sutures are pulled ab interno and tightened for optimum IOL centration. The sutures and exposed knots are imbedded within the scleral groove and sealed with fibrin glue. This 4-point scleral fixation technique was performed uneventfully in 9 cases (4 men, 5 women; mean age 71.4 years ± 12.2 [SD]) and the PC IOL was stable for 10 months (range 8 months to 1 year) with no signs of IOL subluxation, dislocation, tilt, or suture-related complications such as erosion or infection.