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To evaluate structural alterations and healing responses in the trabecular meshwork region with optical coherence tomography (AS-OCT) following after gonioscopy assisted transluminal trabeculotomy (GATT) and microincisional trabeculectomy (MIT). 73 eyes of 67 patients (M:F = 45:22) with ≥6 months of follow-up after MIT (n = 41) or GATT (n = 32) with or without combined cataract surgery were included for this prospective study. The angle as seen on AS-OCT at 1, 3, 6 months after surgery were evaluated for structural alterations like peripheral anterior synechiae (PAS), hyphema, and hyperreflective scarring responses. The scarring was graded according to the linear extent measured from the centre of the trabecular meshwork (TM) gutter to the sclera/cornea as mild (<250μ), moderate (250-500μ), and severe(˃500μ), while the pattern of scarring was graded as open saucer/gutter, closed gutter, and trench pattern. The association of the need for medication or surgical outcome and clinical variables and AS-OCT parameters including the pattern and severity of scarring were analysed using multivariate regression. All eyes achieved significant reduction of IOP and number of medications with a final IOP of 15±3.2mm Hg at a mean follow-up of 8±32. months. While mild scarring was seen more common in MIT, severe scarring was seen in >65% of GATT eyes compared to 31% of MIT eye, p<0.001. An open saucer was equally seen in MIT and GATT while the trench pattern was more commonly seen in GATT eyes (>50%). Severe scarring in a trench pattern seemed to predict the need for medications for IOP control, though they independently did not seem to influence the final IOP or surgical outcome. A severe form of scarring in a trench pattern on AS-OCT predicted the need for glaucoma medications after MIGS surgery. Regular monitoring of the scarring responses by AS-OCT and clinical examination are necessary to identify those at need for medications after MIGS.

To evaluate the clinical applicability of intraoperative predictors for surgical outcomes after gonioscopy-assisted transluminal trabeculotomy (GATT) and microincisional trabeculectomy (MIT). Consecutive patients with primary, or secondary glaucoma (trauma, aphakic, or status post-retinal surgeries) with uncontrolled IOP>21mm Hg, who were scheduled to undergo GATT or MIT with or without significant cataract surgery, at a tertiary eye centre in East India between September 2021 to March 2023, were included. All surgeries were done by a single surgeon. Blanching and Trypan blue (0.4%) staining after intracameral injection using a 25 canula, were analysed in each video. The extent/pattern of blanching and blue staining in each eye was analysed objectively using an overlay of a circle with 12 sectors and a protractor tool to quantify the degrees or quadrants of blanching/staining. Multivariate regression was used to identify predictors for surgical success or the need for medications after surgery. Of 167 eyes that were included (male: female- 134: 33), 49 eyes and 118 eyes underwent GATT and MIT, respectively, with 81 of 167 eyes undergoing concurrent cataract surgery. All eyes had a significant reduction in the number of medications after surgery. Blanching was seen in 154 of 167 eyes in a mean of 2±1.8 quadrants with 41% of eyes showing a blanching effect in >3 quadrants. Of 99 of 167 eyes where Trypan blue staining was assessed, staining in a venular, diffuse haze, or reticular pattern of staining was seen in 73 eyes, 26 eyes showed blue staining in >2 quadrants, with 16% staining in >3 quadrants. Surgical success was not predicted by the quadrants of blanching, blue staining, or other clinical variables (age, visual field, baseline intraocular pressure, type of surgery). The variables significantly predicting the need for medications included blanch (r = -0.1, p = 0.03), and blue staining (r = -0.1, p = 0.04) in <2 quadrants. Blanching and Trypan blue staining in >2 quadrants after GATT or MIT can serve as surrogate predictors for the need for medications. However more studies are mandated to find predictors for surgical success after GATT or MIT.

To evaluate changes in central corneal thickness (CCT) following vitrectomy. All consecutive old and new patients referred to glaucoma services for possible secondary glaucoma after vitrectomy and who had undergone corneal pachymetry between July 2013 to June 2020, were included. The eye that developed elevated intraocular pressure (IOP) and was diagnosed clinically as glaucoma after vitrectomy, was labelled as the \"affected\" eye. The contralateral eye of the patient with normal IOP and no history of vitrectomy was labelled as the \"control\" eye. The difference in CCT in the affected eye and the contralateral control eye (ΔCCT) and CCT were compared between different age groups. Correlation of CCT in the affected eye with age, diagnosis, type of surgery done, lens status and pre-existing glaucoma was done using multivariate regression analysis. Of 127 eyes of 120 patients (M:F = 85:35), the average CCT in the affected eye was significantly higher than the unaffected contralateral control eye (p<0.0001). The ΔCCT in eyes presenting at an age <25 years was higher (median 582, 497-840) than those that presented later (median 518, 384-755), p <0.0001, with maximum ΔCCT seen in eyes that had undergone vitrectomy at age<12 years. The CCT in the affected eye was significantly higher in aphakic eyes (588±81.6 microns) than in pseudophakic eyes (552±79.03 microns), p = 0.03. On multivariate analysis, age<25 years remained as a significant influencer of CCT in the affected eye (β = -1.7, p<0.001, R2 = 28.3%). Young age group<25 years are more prone to corneal remodelling and CCT changes after vitrectomy.

Autoxidation of pyrogallol in alkaline medium is characterized by increases in oxygen consumption, absorbance at 440 nm, and absorbance at 600 nm. The primary products are H 2 O 2 by reduction of O 2 and pyrogallol– ortho -quinone by oxidation of pyrogallol. About 20 % of the consumed oxygen was used for ring opening leading to the bicyclic product, purpurogallin–quinone (PPQ). The absorbance peak at 440 nm representing the quinone end-products increased throughout at a constant rate. Prolonged incubation of pyrogallol in alkali yielded a product with ESR signal. In contrast the absorbance peak at 600 nm increased to a maximum and then declined after oxygen consumption ceased. This represents quinhydrone charge-transfer complexes as similar peak instantly appeared on mixing pyrogallol with benzoquinones, and these were ESR-silent. Superoxide dismutase inhibition of pyrogallol autoxidation spared the substrates, pyrogallol, and oxygen, indicating that an early step is the target. The SOD concentration-dependent extent of decrease in the autoxidation rate remained the same regardless of higher control rates at pyrogallol concentrations above 0.2 mM. This gave the clue that SOD is catalyzing a reaction that annuls the forward electron transfer step that produces superoxide and pyrogallol-semiquinone, both oxygen radicals. By dismutating these oxygen radicals, an action it is known for, SOD can reverse autoxidation, echoing the reported proposal of superoxide:semiquinone oxidoreductase activity for SOD. The following insights emerged out of these studies. The end-product of pyrogallol autoxidation is PPQ, and not purpurogallin. The quinone products instantly form quinhydrone complexes. These decompose into undefined humic acid-like complexes as late products after cessation of oxygen consumption. SOD catalyzes reversal of autoxidation manifesting as its inhibition. SOD saves catechols from autoxidation and extends their bioavailability.

To evaluate the short-term clinical outcomes of microincisional trabeculectomy (MIT), a new technique of ab-interno trabeculectomy. Consecutive patients with open-angle glaucoma identified from the hospital database that underwent MIT with or without cataract surgery between September 2021 to June 2022 at a tertiary eye centre in East India, were screened. Those with a follow-up of < 6 months or with incomplete data were excluded. MIT was done ab-interno using microscissors and microforceps in 2-4 clock hours of the nasal angle via a temporal incision. The intraocular pressure (IOP) reduction at 6 months, and reduction in the number of medications after surgery were analysed. Surgical success (IOP>6 and <22 mm Hg), complications, angle features on anterior segment optical coherence tomography (ASOCT), and the need for additional surgeries were analysed. We included thirty-two eyes of 32 patients with open-angle glaucoma (including n = 9 eyes that underwent concurrent cataract surgery) with a preoperative mean IOP of 22 ±11.1 mm Hg and visual field index of 47±37.9%. All eyes achieved >30% IOP reduction, with a final IOP of 14±6.9 mm Hg at 6 months. Surgical success in 31 of 32 eyes with complete success seen in 28 eyes with none of the eyes requiring >1 medication for IOP control. Hyphema was seen in 4 eyes, while transient IOP spikes at 1 day-1 month were seen in 5 eyes, none of which required any additional interventions. One eye with persistent raised IOP at 1 month required incisional trabeculectomy for uncontrolled IOP with 2 medications. MIT, a new technique of ab-interno trabeculectomy, is effective in terms of IOP control and reduction in the number of medications while having fewer complications. Long-term studies comparing the efficacy of MIT with incisional trabeculectomy, or other procedures are warranted in the future.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

To examine ultrastructural changes in the trabecular meshwork (TM) in patients with primary and secondary glaucoma using scanning electron microscopy (SEM). This was a qualitative descriptive hospital-based study on the ultrastructure of the TM. Pure TM samples were collected after microincisional trabeculectomy from 26 patients with primary or secondary glaucoma and 10 control samples from eye bank donor corneas. SEM was used to analyze structural changes in the TM beams, corneoscleral meshwork (CSM), and juxtacanalicular (JCT) regions. Morphological features were compared between groups and correlated with histopathological findings. SEM revealed flattened and broadened TM beams in the JCT, resembling controls, often with a dumbbell configuration. Histopathological examination (HPE) and SEM showed rounded TM beams with considerable thinning, especially in primary angle-closure glaucoma (PACG), compared to primary open-angle (POAG) and pseudoexfoliation glaucoma (XFG). Maximum thinning in all primary glaucoma occurred in the CSM region, with minimal changes in the JCT region despite a reduction in cellularity in both regions. In steroid glaucoma, amorphous, glistening material was found on the TM beams in the JCT and CSM. XFG eyes displayed vesicular bodies adjacent to fibrillar material scattered diffusely over the TM beams, particularly in the CSM, differing from the platelet clumps seen in regular blood clots. TM beam thinning in primary glaucoma primarily affects the CSM region, sparing the JCT region. Amorphous deposits or vesicular bodies, seen only in steroid-induced glaucoma and XFG, suggest different mechanisms of TM damage in these glaucoma types.

Pseudoexfoliation (PXF) is a unique form of glaucoma characterized by accumulation of exfoliative material in the eyes. Changes in tear profile in disease stages may give us insights into molecular mechanisms involved in causing glaucoma in the eye. All patients were categorized into three main categories; pseudoexfoliation (PXF), pseudoexfoliation glaucoma (PXG) and cataract, which served as control. Cytokines, transforming growth factor β1 (TGFβ1), matrix metalloproteases (MMPs) and fibronectin (FN1) were assessed with multiplex bead assay, enzyme-linked immunosorbent assay (ELISA), gelatin zymography, and immunohistochemistry (IHC) respectively in different ocular tissues such as tears, tenon's capsule, aqueous humor (AH) and serum samples of patients with PXF stages. We found that TGFβ1, MMP-9 and FN1 protein expression were upregulated in tears, tenon's capsule and AH samples in PXG compared to PXF, though the MMP-9 protein activity was downregulated in PXG compared with control or PXF. We have also found that in PXG tears sample the fold change of TGF-α (Transforming Growth Factor-α), MDC (Macrophage Derived Chemokine), IL-8 (Interleukin-8), VEGF (Vascular Endothelial Growth Factor) were significantly downregulated and the levels of GM-CSF (Granulocyte Macrophage Colony Stimulating Factor), IP-10 (Interferon- γ produced protein-10) were significant upregulated. While in AH; IL-6 (Interleukin-6), IL-8, VEGF, IFN-a2 (Interferon- α2), GRO (Growth regulated alpha protein) levels were found lower and IL1a (Interleukin-1α) level was higher in PXG compared to PXF. And in serum; IFN-a2, Eotaxin, GM-CSF, Fractalkine, IL-10 (Interleukin-10), IL1Ra (Interleukin-1 receptor antagonist), IL-7 (Interleukin-7), IL-8, MIP1β (Macrophage Inflammatory Protein-1β), MCP-1 (Monocyte Chemoattractant Protein-1) levels were significantly upregulated and PDGF-AA (Platelet Derived Growth Factor-AA) level was downregulated in the patients with PXG compared to PXF. Altered expression of these molecules in tears may therefore be used as a signal for onset of glaucoma or for identifying eyes at risk of developing glaucoma in PXF.

Mammalian embryogenesis requires rapid growth and proper metabolic regulation 1 . Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development 2 , 3 . Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle 4 , 5 . LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document individualized metabolic programmes in developing organs in utero. Metabolomics analysis of the mouse embryo shows a metabolic shift towards the tricarboxylic acid cycle between gestational days 10.5 and 11.5, leading to the subsequent development of organ-specific metabolic programmes.