Publications by authors named "Adrian Koh"

How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo-electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive.

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Autoimmune retinopathy (AIR) is a rare, potentially blinding retinal disease that remains a challenging condition to manage when resistant to conventional immune-modulatory approaches. We report clinical and electrophysiological improvement in a 49-year-old patient who underwent an autologous hematopoietic stem cell transplant (aHSCT) for thymoma-associated AIR after experiencing progressive disease despite receiving periocular and systemic steroids, mycophenolate mofetil, baricitinib, tacrolimus, bortezomib, rituximab, plasmapheresis, and intravenous immunoglobulin. The aHSCT had two stages: (i) peripheral blood stem cell harvest following mobilization with cyclophosphamide and granulocyte colony-stimulating factor, and (ii) conditioning regimen with plasmapheresis, rituximab, cyclophosphamide, and anti-thymocyte globulin high-dose therapy, followed by autologous hematopoietic cell infusion of 5.

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A panel of 21 international experts are formed by the Asia-Pacific Vitreo-retina Society to work out the consensus and guidelines on polypoidal choroidal vasculopathy (PCV). PCV is a common subtype of neovascular age-related macular degeneration and is more prevalent in Asian populations. Recent advancement in imaging technology allows greater understanding of the disease process of PCV.

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Introduction: Neovascular age-related macular degeneration is a global public-health concern, associated with a considerable burden to individuals, healthcare systems, and society. The objective of this study was to understand different perspectives on the challenges associated with the clinical management of neovascular age-related macular degeneration, which could elucidate measures to comprehensively improve clinical care and outcomes.

Methods: A survey was carried out of patients with neovascular age-related macular degeneration, their providers, and clinic staff in 77 clinics across 24 countries on six continents, from a diverse range of healthcare systems, settings, and reimbursement models.

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Practice patterns for neovascular age-related macular degeneration (nAMD) have evolved from the landmark registration trials of vascular endothelial growth factor (VEGF) inhibitors. Non-monthly regimens like treat-and-extend (T&E) have become popular due to their effectiveness in clinical practice. T&E regimens attempt to limit the burden of visits and treatments by allowing progressively longer treatment intervals, but in so doing, are potentially associated with the expense of treating quiescent disease.

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Article Synopsis
  • The paper looks at how inherited retinal diseases (IRD) are diagnosed and treated in the Asia-Pacific region.
  • They surveyed 36 centers about their practices, including how they collect patient information and provide help for low vision.
  • The results showed there are important gaps, like many centers not having a database for patients, not enough genetic counselors, and a need for better support for low-vision rehabilitation.
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Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization.

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Cyanobacteria use large antenna complexes called phycobilisomes (PBSs) for light harvesting. However, intense light triggers non-photochemical quenching, where the orange carotenoid protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood.

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Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.

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The signal recognition particle (SRP) is a critical component in protein sorting pathways in all domains of life. Human SRP contains six proteins bound to the 7S RNA and their structures and functions have been mostly elucidated. The SRP68/72 dimer is the largest SRP component and is essential for SRP function.

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Article Synopsis
  • The Asia-Pacific region, housing about 60% of the world's population, lacks extensive knowledge about hereditary eye diseases, necessitating a regional collaboration to enhance precision medicine for affected patients.
  • The Asia-Pacific Inherited Eye Disease (APIED) network, consisting of 55 members from 35 centers across 12 countries, aims to address these gaps in understanding inherited retinal diseases (IRDs) by bringing together experts in the field.
  • The network's goals include improving genetic diagnosis of IRDs, standardizing phenotyping practices, and creating high-quality patient registries to support care and research in both regional and international contexts.*
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Aim: To derive a Malaysia guideline and consensus as part of the Malaysia Retina Group's efforts for diagnosis, treatment, and best practices of diabetic macular edema (DME). The experts' panel suggests that the treatment algorithm to be divided into groups according to involvement the central macula. The purpose of DME therapy is to improve edema and achieve the best visual results with the least amount of treatment load.

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There have been recent advances in basic research and clinical studies in polypoidal choroidal vasculopathy (PCV). A recent, large-scale, population-based study found systemic factors, such as male gender and smoking, were associated with PCV, and a recent systematic review reported plasma C-reactive protein, a systemic biomarker, was associated with PCV. Growing evidence points to an association between pachydrusen, recently proposed extracellular deposits associated with the thick choroid, and the risk of development of PCV.

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The aim of this review is to identify the common characteristics and prognoses of different subtypes of neovascular age-related macular degeneration (nAMD). We also propose recommendations on how to tailor treatments to the subtype of neovessels to optimise patient outcomes. The authors, selected members of the Vision Academy, met to discuss treatment outcomes in nAMD according to macular neovascularisation (MNV) subtypes, using evidence from a literature search conducted on the PubMed database (cut-off date: March 2019).

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Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated.

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Introduction: Neovascular age-related macular degeneration (nAMD) is characterized by exudation of fluid from abnormally growing blood vessels in the macula. Anti-vascular endothelial growth factor (VEGF) therapy is standard treatment for nAMD. Fluid resolution is used both as an indicator of disease control and to guide the frequency of treatment because of anti-VEGF therapy effectiveness in reducing neovascularization-related exudation.

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Cryo-electron microscopy (cryo-EM) has been established as a routine method for protein structure determination during the past decade, taking an ever-increasing share of published structural data. Recent advances in TEM technology and automation have boosted both the speed of data collection and quality of acquired images while simultaneously decreasing the required level of expertise for obtaining cryo-EM maps at sub-3 Å resolutions. While most of such high-resolution structures have been obtained using state-of-the-art 300 kV cryo-TEM systems, high-resolution structures can be also obtained with 200 kV cryo-TEM systems, especially when equipped with an energy filter.

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Purpose: To develop a consensus nomenclature for reporting OCT angiography (OCTA) findings in retinal vascular disease (e.g., diabetic retinopathy, retinal vein occlusion) by international experts.

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Objective: To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies.

Design: Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328).

Participants: The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit.

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Purpose: Review and provide consensus recommendations on use of treat-and-extend (T&E) regimens for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) management with relevance for clinicians in the Asia-Pacific region.

Methods: A systematic search of MEDLINE, EMBASE, and Cochrane databases, and abstract databases of the Asia-Pacific Vitreo-retina Society, European Society of Retina Specialists, American Academy of Ophthalmology, and Controversies in Ophthalmology: Asia-Australia congresses, was conducted to assess evidence for T&E regimens in nAMD. Only studies with ≥100 study eyes were included.

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Importance: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed.

Methods: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin.

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Purpose: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study.

Design: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration.

Methods: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg.

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Article Synopsis
  • The study investigates how COVID-19 affected the prognosis of patients with two eye conditions: neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), focusing on treatment management during the pandemic.
  • It includes data from 130 nAMD patients and 76 PCV patients treated between December 2019 and August 2020, analyzing factors like visual acuity and treatment delays.
  • Results show that patients who experienced treatment delays suffered worse visual outcomes and a higher rate of complications, highlighting the need for consistent follow-up and timely care during health crises.
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Purpose: To develop and validate OCT and color fundus photography (CFP) criteria in differentiating polypoidal choroidal vasculopathy (PCV) from typical neovascular age-related macular degeneration (nAMD) in eyes with suboptimal response to anti-vascular endothelial growth factor (VEGF) monotherapy and to determine whether OCT alone can be used to guide photodynamic therapy (PDT) treatment.

Design: Clinical study evaluating diagnostic accuracy.

Participants: Patients with nAMD who received 3-month anti-VEGF monotherapy but had persistent activity defined as subretinal fluid or intraretinal fluid at month 3 assessments.

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