Fucosylated Chondroitin Sulfates with Rare Disaccharide Branches from the Sea Cucumbers Psolus peronii and Holothuria nobilis: Structures and Influence on Hematopoiesis.

Two fucosylated chondroitin sulfates were isolated from the sea cucumbers Psolus peronii and Holothuria nobilis using a conventional extraction procedure in the presence of papain, followed by anion-exchange chromatography on DEAE-Sephacel. Their composition was characterized in terms of quantitative monosaccharide and sulfate content, and structures were mainly elucidated using 1D- and 2D-NMR spectroscopy. As revealed by the data of the NMR spectra, both polysaccharides along with the usual fucosyl branches contained rare disaccharide branches α-D-GalNAc4S6R-(1→2)-α-L-Fuc3S4R → attached to O-3 of the GlcA of the backbone (R = H or SO3-). The polysaccharides were studied as stimulators of hematopoiesis in vitro using mice bone marrow cells as the model. The studied polysaccharides were shown to be able to directly stimulate the proliferation of various progenitors of myelocytes and megakaryocytes as well as lymphocytes and mesenchymal cells in vitro. Therefore, the new fucosylated chondroitin sulfates can be regarded as prototype structures for the further design of GMP-compatible synthetic analogs for the development of new-generation hematopoiesis stimulators.

Influence of the Phase Composition of Titanium Alloys on Cell Adhesion and Surface Colonization.

The pivotal role of metal implants within the host's body following reconstructive surgery hinges primarily on the initial phase of the process: the adhesion of host cells to the implant's surface and the subsequent colonization by these cells. Notably, titanium alloys represent a significant class of materials used for crafting metal implants. This study, however, marks the first investigation into how the phase composition of titanium alloys, encompassing the volume fractions of the α, ß, and ω phases, influences cell adhesion to the implant's surface. Moreover, the research delves into the examination of induced hemolysis and cytotoxicity. To manipulate the phase composition of titanium alloys, various parameters were altered, including the chemical composition of titanium alloys with iron and niobium, annealing temperature, and high-pressure torsion parameters. By systematically adjusting these experimental parameters, we were able to discern the distinct impact of phase composition. As a result, the study unveiled that the colonization of the surfaces of the examined Ti-Nb and Ti-Fe alloys by human multipotent mesenchymal stromal cells exhibits an upward trend with the increasing proportion of the ω phase, concurrently accompanied by a decrease in the α and ß phases. These findings signify a new avenue for advancing Ti-based alloys for both permanent implants and temporary fixtures, capitalizing on the ability to regulate the volume fractions of the α, ß, and ω phases. Furthermore, the promising characteristics of the ω phase suggest the potential emergence of a third generation of biocompatible Ti alloys, the ω-based materials, following the first-generation α-Ti alloys and second-generation ß alloys.

Development of Bioactive Scaffolds for Orthopedic Applications by Designing Additively Manufactured Titanium Porous Structures: A Critical Review.

We overview recent findings achieved in the field of model-driven development of additively manufactured porous materials for the development of a new generation of bioactive implants for orthopedic applications. Porous structures produced from biocompatible titanium alloys using selective laser melting can present a promising material to design scaffolds with regulated mechanical properties and with the capacity to be loaded with pharmaceutical products. Adjusting pore geometry, one could control elastic modulus and strength/fatigue properties of the engineered structures to be compatible with bone tissues, thus preventing the stress shield effect when replacing a diseased bone fragment. Adsorption of medicals by internal spaces would make it possible to emit the antibiotic and anti-tumor agents into surrounding tissues. The developed internal porosity and surface roughness can provide the desired vascularization and osteointegration. We critically analyze the recent advances in the field featuring model design approaches, virtual testing of the designed structures, capabilities of additive printing of porous structures, biomedical issues of the engineered scaffolds, and so on. Special attention is paid to highlighting the actual problems in the field and the ways of their solutions.

Bioactivity Features of a Zn-1%Mg-0.1%Dy Alloy Strengthened by Equal-Channel Angular Pressing.

The structure, phase composition, corrosion and mechanical properties, as well as aspects of biocompatibility in vitro and in vivo, of a Zn-1%Mg-0.1%Dy alloy after equal-channel angular pressing (ECAP) were studied. The structure refinement after ECAP leads to the formation of elongated α-Zn grains with a width of ~10 µm and of Mg- and Dy-containing phases. In addition, X-ray diffraction analysis demonstrated that ECAP resulted in the formation of the basal texture in the alloy. These changes in the microstructure and texture lead to an increase in ultimate tensile strength up to 262 ± 7 MPa and ductility up to 5.7 ± 0.2%. ECAP slows down the degradation process, apparently due to the formation of a more homogeneous microstructure. It was found that the alloy degradation rate in vivo after subcutaneous implantation in mice is significantly lower than in vitro ones. ECAP does not impair biocompatibility in vitro and in vivo of the Zn-1%Mg-0.1%Dy alloy. No signs of suppuration, allergic reactions, the formation of visible seals or skin ulcerations were observed after implantation of the alloy. This may indicate the absence of an acute reaction of the animal body to the Zn-1%Mg-0.1%Dy alloy in both states.

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte "on-target off-tumor" reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.

Glycosaminoglycans from the Starfish Lethasterias fusca: Structures and Influence on Hematopoiesis.

Crude anionic polysaccharides extracted from the Pacific starfish Lethasterias fusca were purified by anion-exchange chromatography. The main fraction LF, having MW 14.5 kDa and dispersity 1.28 (data of gel-permeation chromatography), was solvolytically desulfated and giving rise to preparation LF-deS with a structure of dermatan core [→3)-ß-d-GalNAc-(1→4)-α-l-IdoA-(1→]n, which was identified according to NMR spectroscopy data. Analysis of the NMR spectra of the parent fraction LF led to identification of the main component as dermatan sulfate LF-Derm →3)-ß-d-GalNAc4R-(1→4)-α-l-IdoA2R3S-(1→ (where R was SO3 or H), bearing sulfate groups at O-3 or both at O-2 and O-3 of α-l-iduronic acid, as well as at O-4 of some N-acetyl-d-galactosamine residues. The minor signals in NMR spectra of LF were assigned as resonances of heparinoid LF-Hep composed of the fragments →4)-α-d-GlcNS3S6S-(1→4)-α-l-IdoA2S3S-(1→. The 3-O-sulfated and 2,3-di-O-sulfated iduronic acid residues are very unusual for natural glycosaminoglycans, and further studies are needed to elucidate their possible specific influence on the biological activity of the corresponding polysaccharides. To confirm the presence of these units in LF-Derm and LF-Hep, a series of variously sulfated model 3-aminopropyl iduronosides were synthesized and their NMR spectra were compared with those of the polysaccharides. Preparations LF and LF-deS were studied as stimulators of hematopoiesis in vitro. Surprisingly, it was found that both preparations were active in these tests, and hence, the high level of sulfation is not necessary for hematopoiesis stimulation in this particular case.

Structure, Biodegradation, and In Vitro Bioactivity of Zn-1%Mg Alloy Strengthened by High-Pressure Torsion.

The effect of high-pressure torsion (HPT) on the microstructure, phase composition, mechanical characteristics, degradation rate, and bioactive properties of the Zn-1%Mg alloy is studied. An ultrafine-grained (UFG) structure with an average grain size of α-Zn equal to 890 ± 26 nm and grains and subgrains of the Mg2Zn11 and MgZn2 phases with a size of 50-100 nm are formed after HPT. This UFG structure leads to an increase in the ultimate tensile strength of the alloy by ~3 times with an increase in elongation to 6.3 ± 3.3% due to the formation of a basal texture. The study of corrosion resistance did not show a significant effect of HPT on the degradation rate of the alloy. In addition, no significant changes in the bioactivity of the alloy after HPT: hemolysis, cellular colonization and Escherichia coli growth inhibition.

Perspectives for the Use of Fucoidans in Clinical Oncology.

Fucoidans are natural sulfated polysaccharides that have a wide range of biological functions and are regarded as promising antitumor agents. The activity of various fucoidans and their derivatives has been demonstrated in vitro on tumor cells of different histogenesis and in experiments on mice with grafted tumors. However, these experimental models showed low levels of antitumor activity and clinical trials did not prove that this class of compounds could serve as antitumor drugs. Nevertheless, the anti-inflammatory, antiangiogenic, immunostimulating, and anticoagulant properties of fucoidans, as well as their ability to stimulate hematopoiesis during cytostatic-based antitumor therapy, suggest that effective fucoidan-based drugs could be designed for the supportive care and symptomatic therapy of cancer patients. The use of fucoidans in cancer patients after chemotherapy and radiation therapy might promote the rapid improvement of hematopoiesis, while their anti-inflammatory, immunomodulatory, and anticoagulant effects have the potential to improve the quality of life of patients with advanced cancer.

Intracorneal knot or flange depot fixation: new transscleral technique for intraocular lens fixation.

A new surgical technique of transscleral-intracorneal suture fixation of intraocular lenses with suture ends located within the transparent corneal or corneal-limbal paracentesis is reported. This new technique significantly reduces scleral and conjunctival trauma, is minimally invasive, is simple to perform, is not associated with complicated intraocular surgical maneuvers, and precludes suture knot, flange, and suture-end erosion. The internal part of the corneal stroma or corneal-limbal area serves as a secure depot for suture-end fixation with durable resistance. The technique enables visualization of the exact position of suture ends over time.

Effect of Descemet Membrane Endothelial Keratoplasty Graft Storage Time on Graft Elasticity.

PURPOSE: The purpose of this study was to evaluate the effect of Descemet membrane endothelial keratoplasty (DMEK) graft storage time on its elastic properties, measured using atomic force microscopy (AFM). METHODS: Twenty human corneas (from 10 donors), unsuitable for transplantation, were obtained from the eye bank (S. Fyodorov Eye Microsurgery State Institution, Moscow). Ten DMEK grafts were prepared and stored in the corneal storage medium, Optisol-GS at 4°C after preparation, and AFM analysis was performed within 12 hours after preparation (group A). Ten paired corneas from the respective donors were stored in Optisol-GS at 4°C for 1 week after preparation before AFM analysis (group B). Data were analyzed using the Hertz model for the evaluation of the Young modulus of elasticity. RESULTS: Force-distance curve analysis showed an increase in the Young modulus of elasticity in group B in comparison with that in group A, and the mean values were 10.4 ± 1.8 kPa and 6.77 ± 2.25 kPa, respectively (P < 0.001). There was no correlation between the Young modulus of elasticity and donor age (r = 0.110, P = 0.644), endothelial cell count (r = -0.145, P = 0.541), and procurement interval (r = 0.14, P = 0.755). CONCLUSIONS: A longer graft storage time in cold storage medium was found to significantly reduce the elasticity of the DMEK graft. Clinically, this could potentially influence the unfolding of the DMEK graft within the anterior chamber during surgery and the postoperative detachment rate.

Depolymerization of a fucosylated chondroitin sulfate from Cucumaria japonica: Structure and activity of the product.

Fucosylated chondroitin sulfate CJ from the body wall of sea cucumber Cucumaria japonica was depolymerized by the treatment with H2O2 in the presence of Cu(OAc)2. The molecular weight of the polysaccharide was decreased from 32 kDa to 5 kDa. The product CJ-DP was shown to contain l-Fuc, d-GalNAc, d-GlcA, and sulfate in molar proportions of 0.96:0.90:1.00:5.4, which were quite similar to those of the parent polysaccharide CJ. The NMR analysis revealed that CJ-DP, like the parent polysaccharide CJ, consisted of both branched →4)-[3-O-α-l-Fuc]-ß-d-GlcA-(1 â†’ 3)-ß-d-GalNAc-(1→ and linear →4)-ß-d-GlcA-(1 â†’ 3)-ß-d-GalNAc-(1→ repeating blocks. Sulfate groups occupy O-4 and the majority of O-6 of GalNAc, as well as O-3 of GlcA, in linear blocks and different positions in Fuc branches. This result indicates that depolymerization practically does not diminish the amount of branches and sulfate groups in the product. Both polysaccharides CJ and CJ-DP demonstrated anticoagulant and hematopoiesis-stimulatory activities in vitro.

Antiproliferative, proapoptotic, and tumor-suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts.

The aim of this study was to explore the mechanisms of action of alsevirone in prostate cancer (PC) in vitro and in vivo: CYP17A1 inhibition, cytotoxic, apoptotic, and antitumor effects in comparison with abiraterone. The CYP17A1-inhibitory activity was investigated in rat testicular microsomes using high-performance liquid chromatography. Testosterone levels were evaluated using enzyme-linked immunoassay. IC50 values were calculated for PC3, DU-145, LNCaP, and 22Rv1 cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. The antitumor effect in vivo was studied in DU-145 and 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone reduced the CYP17A1-inhibitory activity by 98% ± 0.2%. A statistically significant reduction in the testosterone concentration in murine blood was recorded after the 7th administration of 300 mg/kg alsevirone at 0.31 ± 0.03 ng/ml (p < .001) versus 0.98 ± 0.22 ng/ml (p = .392) after abiraterone administration and 1.52 ± 0.49 ng/ml in control animals. Alsevirone was more cytotoxic than abiraterone in DU-145, LNCaP, and 22Rv1 cells, with IC50 values of 23.80 ± 1.18 versus 151.43 ± 23.70 µM, 22.87 ± 0.54 versus 28.80 ± 1.61 µM, and 35.86 ± 5.63 versus 109.87 ± 35.15 µM, respectively. Alsevirone and abiraterone significantly increased annexin V-positive, caspase 3/7-positive, and activated Bcl-2-positive cells. In 22Rv1 xenografts, alsevirone 300 mg/kg × 10/24 h per os inhibited tumor growth: on Day 9 of treatment, tumor growth inhibition = 59% (p = .022). Thus, alsevirone demonstrated significant antitumor activity associated with CYP17A1 inhibition, apoptosis in PC cells, and testosterone reduction.

Corectopia grading: A novel classification system.

OBJECTIVES: To present and validate the novel grading system for objective classification of corectopia. SUBJECTS AND METHODS: We evaluated 28 eyes of 28 patients with or without corectopia and validated the grading and classification system for corectopia according to three major criteria: (i) direction, (ii) extent, and (iii) alteration of mydriasis. Intraclass correlation coefficient (ICC) and inter-rater agreement between 7 inexperienced and 1 experienced ophthalmologist against a golden standard (GS) were calculated. RESULTS: The ICC for the 7 inexperienced ophthalmologists regarding the grading of direction and centration of the pupil was 0.83 (95% confidence interval (CI), 0.74 to 0.90; p < .001) and 0.57 (95% CI, 0.43 to 0.72; p < .001), respectively. The inter-rater agreement was the same or almost the same in cases of pupil decentration between the inexperienced, experienced ophthalmologists and the GS (k = 0.82; 95% CI, 0.64-1.00; p < .001). In assessing the direction of pupil displacement, the inter-rater agreement was almost perfect between the inexperienced (k = 0.93; 95% CI, 0.84-1.00; p < .001) and experienced (k = 0.92; 95% CI: 0.82-1.02; p < .001) ophthalmologists and the GS. CONCLUSION: The first detailed clinical classification is proposed for objective corectopia grading particularly relevant in documenting and assessing progressive disease. It was confirmed to be acceptable for clinical use by inexperienced and experienced ophthalmologists alike.

Structure Optimization of a Fe-Mn-Pd Alloy by Equal-Channel Angular Pressing for Biomedical Use.

In this work, a Fe-Mn-Pd alloy was produced by methods of equal channel angular pressing (ECAP) in order to obtain an alloy with a high rate of degradation for the development of biodegradable devices. Special efforts were made to the obtaining of an ultrafine-grained structure of alloys in a fully austenitic state at temperatures of 300 °C and 450 °C. Further investigation of its effect on the corrosion rate and mechanical properties was carried out. The formation of an austenitic structure with structural element sizes of 100-250 nm after deformation was confirmed by X-ray diffraction analysis. ECAP proved to be the reason for a significant increase in strength with maximum σUTS = 1669 MPa and σYS = 1577 MPa while maintaining satisfactory plasticity. The alloy degradation rate was investigated using the potentiodynamic polarization analysis. The corrosion rate of the alloy after ECAP (~1 mm/y) is higher than that of the coarse-grained state and significantly higher than that of annealed iron (~0.2 mm/y). ECAP in both modes did not impair the biocompatibility of the Fe-Mn-Pd alloy and the colonization of the sample surface by cells.

Chondroitin Sulfate and Fucosylated Chondroitin Sulfate as Stimulators of Hematopoiesis in Cyclophosphamide-Induced Mice.

The immunosuppression and inhibition of hematopoiesis are considered to be reasons for the development of complications after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation. Chondroitin sulfate (CS), isolated from the fish Salmo salar, and fucosylated chondroitin sulfate (FCS), isolated from the sea cucumber Apostichopus japonicus, were studied for their roles as stimulators of hematopoiesis in a model of cyclophosphamide-induced immunosuppression in mice. The recombinant protein r G-CSF was applied as a reference. The studied polysaccharides were shown to stimulate the release of white and red blood cells, as well as platelets from bone marrow in immunosuppressed mice, while r G-CSF was only responsible for the significant increase in the level of leucocytes. The analysis of different populations of leucocytes in blood indicated that r G-CSF mainly stimulated the production of neutrophils, whereas in the cases of the studied saccharides, increases in the levels of monocytes, lymphocytes and neutrophils were observed. The normalization of the level of the pro-inflammatory cytokine IL-6 in the serum and the recovery of cell populations in the spleen were observed in immunosuppressed mice following treatment with the polysaccharides. An increase in the proliferative activity of hematopoietic cells CD34(+)CD45(+) was observed following ex vivo polysaccharide exposure. Further study on related oligosaccharides regarding their potential as promising drugs in the complex prophylaxis and therapy of hematopoiesis inhibition after intensive chemotherapy and allogeneic hematopoietic stem cell transplantation seems to be warranted.

Anti-tumour activity of Mg-6%Ag and Mg-10%Gd alloys in mice with inoculated melanoma.

Cytotoxicity in vitro and anti-tumour activity in vivo of magnesium alloys Mg-6%Ag and Mg-10%Gd was studied. It was shown that specifically designed and thermomechanically processed Mg alloys produced a sizeable cytotoxic effect on PC-3 line tumour cells in vitro through inhibition of their proliferation. A pronounced grain refinement in combination with the formation of second phases and precipitates attained by means of equal-channel angular pressing (ECAP) accellerated the degradation and gave rise to enhanced anti-tumour activity of both alloys. The gadolinium-containing alloy outperformed the silver-containing one substantially. In an in vivo assay, intratumoural implantation of pins made from both alloys in the homogenised and the ECAP states in mice with inoculated B16 melanoma gave rise to an indubitable anti-tumour effect. It was documented in a decrease of Ki-67(+) cells and the occurrence of regions of destruction of tumoural tissue that were filled with gas evolving in the course of biodegradation of the implants. The data obtained suggest that intratumoural implantation of gadolinium-containing magnesium alloys can be considered for therapy of inoperable or chemoresistant forms of cancer.

Late dislocation of the capsular bag-intraocular lens-modified capsular tension ring complex after knotless transscleral suturing using 9-0 polypropylene.

We report a case of late breakage of a 9-0 polypropylene transscleral suture used for fixation of a dislocated capsular bag-intraocular lens-modified capsular tension ring complex in a 52-year-old woman with Marfan syndrome. Breakage occurred despite use of a cow-hitch technique for external and internal fixation. We believe breakage was caused by the suture chafing on the sharp edges of the modified capsular tension ring eyelet. Cross-sectional analysis of Malyugin-modified capsular tension rings from two different manufacturers revealed a difference with respect to radius of curvature. Suturing intraocular implants with relatively sharp edges may cause suture breakage; further studies are needed to identify the critical parameters for the surface quality of sutured intraocular implants.

Five-year results of non-penetrating deep sclerectomy with demineralized cancellous bone xenogenically derived collagen glaucoma implant.

PURPOSE: To investigate the long-term effectiveness of non-penetrating deep sclerectomy (NPDS) with xenogenically derived cancellous bone collagen glaucoma implant (XCB-CGI) implantation in patients with primary open-angle glaucoma (POAG). MATERIALS AND METHODS: Retrospective chart review of patients with POAG stages 2 and 3 was treated with NPDS and XCB-CGI. Follow-up was at 6 months, 1, 2, 3, 4 and 5 years after surgery. Main outcomes were intraocular pressure (IOP) and medication burden. Secondary outcomes were visual acuity, corneal hysteresis (CH), visual field (VF) and optical coherence tomography (OCT) parameter analysis. RESULTS: Among 71 patients (71 eyes), the mean age was 72.7 ± 9.8. Average initial IOP was 27.7 ± 7.9 and average initial med load was 2.36 ± 0.99. At 6 months, 1, 2, 3, 4 and 5 years, the average IOP was 14.9 ± 3.3 mm Hg (46.2% reduction), 15.3 ± 4.0 mm Hg (44.7% reduction), 14.2 ± 3.8 mm Hg (48.7% reduction), 15.2 ± 3.3 mm Hg (45.0% reduction), 15.5 ± 3.3 mm Hg (44.0% reduction) and 14.2 ± 2.8 mm Hg (48.7% reduction), respectively. In 5 years, the success rate was 34% and 67%, without, and with medications (1.8 ± 0.8 meds required), respectively. Visual acuity was not significantly different (P > .05) at all follow-up visits from baseline. Mean CH increased by 2.1 ± 0.8 (P = .05). No glaucomatous deterioration of the VF and OCT parameters was detected in 56 eyes at the 5-year follow-up. CONCLUSION: NPDS with XCB-CGI implantation is an effective procedure to normalize the level of IOP, stabilize glaucomatous changes and decrease the number of meds needed for glaucoma control.

Refractive outcomes following cataract combined with lamellar keratoplasty: femtosecond-DSEK versus microkeratome-DSAEK.

PURPOSE: Prediction of postoperative refraction following posterior lamellar keratoplasty is crucial for choosing proper intraocular lens power in combined surgeries. Femtosecond laser-assisted Descemet stripping endothelial keratoplasty (FS-DSEK) creates thin, planar grafts while microkeratome-assisted Descemet's stripping automated endothelial keratoplasty (DSAEK) creates non-planar, concaved grafts. We evaluated whether this fundamental difference affects the refractive outcomes in cataract surgery combined with FS-DSEK compared to cataract surgery combined with microkeratome-assisted DSAEK. METHODS: A retrospective analysis of 28 patients who underwent FS-DSEK combined with phacoemulsification and intraocular lens (IOL) implantation (group A) compared to 26 patients who underwent microkeratome-assisted DSAEK combined with phacoemulsification and IOL implantation (group B). Pre- and 1-year postoperative best-corrected visual acuity (BCVA), keratometry values, corneal thickness, central-to-peripheral graft thickness ratio (C/P ratio), and target postoperative spherical equivalent (SE) versus actual postoperative SE were analyzed. RESULTS: Target postoperative SE and actual postoperative SE significantly shifted toward hyperopia in group B, but not in group A. Postoperative hyperopic shifts were 0.14 D and 1.13 D in groups A and B, respectively (P < 0.001). BCVA improved after surgery in both groups, with no significant difference between the groups. Postoperative C/P ratio differed significantly between the groups and was negatively correlated with postoperative hyperopic shift (r = - 0.616, P < 0.001). CONCLUSION: Refractive outcomes of cataract surgery combined with FS-DSEK are relatively neutral, whereas those of cataract surgery combined with microkeratome-assisted DSAEK cause significant hyperopic shift. Clinicians should select accordingly an appropriate intraocular lens power when performing these surgeries.

Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy.

In search for new and safer anti-cancer agents, a structurally guided pharmacophore hybridization strategy of two privileged scaffolds, namely diaryl pyrazolines and imidazolidine-2,4-dione (hydantoin), was adopted resulting in a newfangled series of compounds (H1-H22). Herein, a bio-isosteric replacement of "pyrrolidine-2,5-dione" moiety of our recently reported antitumor hybrid incorporating diaryl pyrazoline and pyrrolidine-2,5-dione scaffolds with "imidazoline-2,4-dione" moiety has been incorporated. Complete biological studies revealed the most potent analog among all i.e. compound H13, which was at-least 10-fold more potent compared to the corresponding pyrrolidine-2,5-dione, in colon and breast cancer cells. In-vitro studies showed activation of caspases, arrest of G0/G1 phase of cell cycle, decrease in the expression of anti-apoptotic protein (Bcl-2) and increased DNA damage. In-vivo assay on HT-29 (human colorectal adenocarcinoma) animal xenograft model unveiled the significant anti-tumor efficacy along with oral bioavailability with maximum TGI 36% (i.p.) and 44% (per os) at 50 mg/kg dose. These findings confirm the suitability of hybridized pyrazoline and imidazolidine-2,4-dione analog H13 for its anti-cancer potential and starting-point for the development of more efficacious analogs.