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Lipid remodeling, from fatty acid transport and de novo lipid synthesis, is necessary for megakaryocyte differentiation and platelet production. Dietary saturated fatty acids, impaired fatty acid transport and/or dysfunction in lipid biogenesis can contribute to low platelet counts.
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Ewing sarcoma is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. Ewing sarcoma has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that ubiquitin-specific protease 6 (USP6) functions as a tumor suppressor in Ewing sarcoma, and identified it as the first cell-intrinsic factor to modulate the Ewing sarcoma immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of Ewing sarcoma xenograft growth. USP6 expression in Ewing sarcoma cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK cell-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), providing an additional route for enhanced sensitivity to NK cell killing. Furthermore, USP6-expressing Ewing sarcoma and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein IFNγ secreted by activated NK cells feeds back on USP6/Ewing sarcoma cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous Ewing sarcoma xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the Ewing sarcoma TME to enhance antitumor immunity, and may be exploited for future therapeutic benefit. Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell-intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.
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Neoplasias Ósseas , Tumores Neuroectodérmicos Primitivos Periféricos , Sarcoma de Ewing , Humanos , Animais , Camundongos , Fator Intrínseco , Ligantes , Camundongos Nus , Fator de Indução de Apoptose , Proteases Específicas de Ubiquitina , Microambiente Tumoral , Ubiquitina TiolesteraseRESUMO
Purpose: To ascertain the prevalence and clinical features of the various types of childhood glaucoma at a tertiary eye care hospital in Northern India. Materials and methods: Retrospective chart review of all children less than 16 years of age with childhood glaucoma who presented from 1st April 2014 to 31st March 2019, who was diagnosed to have any subtype of childhood glaucoma as per Childhood Glaucoma Research Network (CGRN) classification and advised appropriate management. Results: Out of 405 children with childhood glaucoma, 36% had primary glaucoma, whereas the rest had secondary glaucoma. Primary congenital glaucoma (PCG) was the most common form of primary glaucoma. Glaucoma associated with acquired conditions was the most common cause of secondary glaucoma. Primary glaucoma was mostly bilateral in contrast to secondary glaucoma. The most common age of presentation with primary glaucoma was <1 year of age, and in children with secondary glaucoma was 11-16 years. On presentation, 80% of eyes had intraocular pressure (IOP) of >20 mm Hg and 70% had cupping of >0.7. Eyes with PCG were primarily managed surgically. Conclusion: In our cohort, PCG was the most common primary childhood glaucoma. Traumatic glaucoma was the most common secondary glaucoma. Since childhood glaucoma is an important cause of visual morbidity in children, its timely diagnosis and prompt management are essential to prevent irreversible visual loss. Clinical significance: Understanding the disease pattern, their presenting features, and the proportion of different types of childhood glaucoma can help in planning appropriate eye care services, create awareness and better allocate resources to plan appropriate management strategies. Screening programs and counseling of parents should also be strengthened. How to cite this article: Dubey S, Jain K, Pegu J, et al. Profile of Childhood Glaucoma Attending a Tertiary Eye Care Center in Northern India. J Curr Glaucoma Pract 2023;17(2):68-74.
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PURPOSE: The study aimed to describe the phenotypic features of retinitis pigmentosa (RP) associated with the previously described EYS C2139Y variant in Singaporeans and establish the importance of this variant as a prevalent cause of RP among East Asians. METHODS: A clinical phenotyping and exome-sequencing study was conducted on consecutive patients with nonsyndromic RP. Epidemiological analysis was performed using Singaporean and global population-based genetic data. RESULTS: A study of 150 consecutive unrelated individuals with nonsyndromic RP found that 87 (58%) of cases had plausible genotypes. A previously described missense variant in the EYS gene, 6416G>A (C2139Y), occurred heterozygously or homozygously in 17 of 150 families (11.3%), all with autosomal recessive RP. Symptom onset in EYS C2139Y-related RP ranged from 6 to 45 years, with visual acuity ranging from 20/20 at 21 years to no light perception by 48 years. C2139Y-related RP had typical findings, including sectoral RP in cases with EYS E2703X in trans . The median age at presentation was 45 years and visual fields declined to less than 20° (Goldmann V4e isopter) by age 65 years. Intereye correlation for visual acuity, fields, and ellipsoid band width was high (r 2 = 0.77-0.95). Carrier prevalence was 0.66% (allele frequency of 0.33%) in Singaporean Chinese and 0.34% in East Asians, suggesting a global disease burden exceeding 10,000 individuals. CONCLUSION: The EYS C2139Y variant is common in Singaporean RP patients and other ethnic Chinese populations. Targeted molecular therapy for this single variant could potentially treat a significant proportion of RP cases worldwide.
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Cegueira , População do Leste Asiático , Proteínas do Olho , Retinose Pigmentar , Idoso , Humanos , Cegueira/diagnóstico , Cegueira/epidemiologia , Cegueira/etnologia , Cegueira/genética , Análise Mutacional de DNA , População do Leste Asiático/genética , Proteínas do Olho/genética , Mutação , Linhagem , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/etnologia , Retinose Pigmentar/genéticaRESUMO
BACKGROUND: Ongoing trials for retinitis pigmentosa (RP) are genotype-specific, with most trials conducted on European cohorts. Due to genetic differences across diverse ancestries and populations, these therapies may not be efficacious in East Asians. MATERIALS AND METHODS: A literature search was conducted from 1966 to September 2022 for cohort studies on East Asian populations reporting on non-syndromic RP genotypes and variants. Population-weighted prevalence was used to determine the genotypes and individual variants across the entire cohort. The carrier prevalence of common variants was compared against those in Europe. RESULTS: A total of 12 articles describing 2,932 clinically diagnosed East Asian RP probands were included. We identified 876 variants across 54 genes. The most common genotypes included USH2A, EYS, RPGR, ABCA4, PRPF31, RHO, RP1, RP2, PDE6B and SNRNP200, with USH2A as the most common (17.1%). Overall, 60.5% of probands with clinically relevant variants were found to have one of the genotypes above, with 543/876 (62.0%) of the variants occurring in these genes. The most frequently reported variant was USH2A missense variant c.2802T>G/p.C934W (4.9%). Carrier prevalence of these variants was significantly different (p < 0.0001) than in Europe. CONCLUSIONS: USH2A was the most commonly affected RP gene in this East Asian cohort, although sub-population analysis revealed distinct genotype prevalence patterns. While the genotypes are similar between East Asia and European cohorts, variants are specific to East Asia. The identification of several prevalent variants in USH2A and EYS provides an opportunity for the development of therapeutics that are relevant for East Asia patients.
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População do Leste Asiático , Proteínas da Matriz Extracelular , Retinose Pigmentar , Humanos , Análise Mutacional de DNA , Genótipo , Mutação , Linhagem , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/genética , Proteínas da Matriz Extracelular/genéticaRESUMO
Psychological distress associated with surgery is an emerging issue. The study was conducted to assess the impact of structured patient education viz-a-viz routine patient education on anxiety and depression levels in patients undergoing elective chest surgery. It is a prospective, double-blind randomized study, conducted from February 2019 to February 2020 at a tertiary care center in India, on patients who underwent elective chest surgeries. A total of 300 patients were randomized using a computer-generated randomization sequence, into 2 equal groups (150 subjects each). Study group included patients who underwent structured patient education (Group A), whereas control group included patients who underwent routine patient education (Group B). The 2 groups were compared for anxiety and depression levels at admission as well as discharge using Hospital Anxiety and Depression Scale. Also, at the time of discharge, the groups were compared for the effectiveness of patient education using a validated Questionnaire B. In comparison to routine education, patients receiving structured education showed significantly lesser scores for anxiety and depression at discharge (P < .001). Also, structured patient education proved to be effective in comparison to the routine education in educating the patients in all parameters as determined by the Questionnaire B (P < .05). It can be concluded that structured educational intervention is strongly recommended in patients undergoing chest surgery which can help alleviate perioperative anxiety and depression. Such intervention helps patient get an understanding of the surgical procedure and assist them in facing the condition in a better way.
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Current understanding of tumor immunosuppressive mechanisms forms the basis for modern day immunotherapies. Immunoregulatory role of platelets in cancer remains largely elusive. Platelets from non-small cell lung cancer (NSCLC) patients revealed a distinct activation phenotype. TREM-like transcript 1 (TLT-1), a platelet protein, was increased along with enhanced extracellular release from NSCLC platelets. The increased platelet TLT-1 was also evident in humanized mice with patient-derived tumors. In immunocompetent mice with syngeneic tumors, TLT-1 binding to T cells, in vivo, led to suppression of CD8 T cells, promoting tumor growth. We identified direct interaction between TLT-1 and CD3ε on T cells, implicating the NF-κB pathway in CD8 T cell suppression. Anti-TLT-1 antibody rescued patients' T cells from platelet-induced suppression ex vivo and reduced tumors in mice in vivo. Clinically, higher TLT-1 correlated with reduced survival of NSCLC patients. Our findings thus identify TLT-1 as a platelet-derived immunosuppressor that suppresses CD8 T cells and demonstrate its therapeutic and prognostic significance in cancer.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Receptores Imunológicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Plaquetas/metabolismo , Linfócitos T CD8-PositivosRESUMO
BACKGROUND: Unfolded protein response (UPR) is a multifaceted signaling cascade that alleviates protein misfolding. Although well studied in nucleated cells, UPR in absence of transcriptional regulation has not been described. Intricately associated with cardiovascular diseases, platelets, despite being anucleate, respond rapidly to stressors in blood. We investigate the UPR in anucleate platelets and explore its role, if any, on platelet physiology and function. METHODS: Human and mouse platelets were studied using a combination of ex vivo and in vivo experiments. Platelet lineage-specific knockout mice were generated independently for each of the 3 UPR pathways, PERK (protein kinase RNA [PKR]-like endoplasmic reticulum kinase), XBP1 (X-binding protein), and ATF6 (activating transcription factor 6). Diabetes patients were prospectively recruited, and platelets were evaluated for activation of UPR under chronic pathophysiological disease conditions. RESULTS: Tunicamycin induced the IRE1α (inositol-requiring enzyme-1alpha)-XBP1 pathway in human and mouse platelets, while oxidative stress predominantly activated the PERK pathway. PERK deletion significantly increased platelet aggregation and apoptosis and phosphorylation of PLCγ2, PLCß3, and p38 MAPK. Deficiency of XBP1 increased platelet aggregation, with higher PLCß3 and PKCδ activation. ATF6 deletion mediated a relatively modest effect on platelet phenotype with increased PKA (protein kinase A). Platelets from diabetes patients exhibited a positive correlation between disease severity, platelet activation, and protein aggregation, with only IRE1α-XBP1 activation. Moreover, IRE1α inhibition increased platelet aggregation, while clinically approved chemical chaperone, sodium 4-phenylbutyrate reduced the platelet hyperactivation. CONCLUSIONS: We show for the first time, that UPR activation occurs in platelets and can be independent of genomic regulation, with selective induction being specific to the source and severity of stress. Each UPR pathway plays a key role and can differentially modulate the platelet activation pathways and phenotype. Targeting the specific arms of UPR may provide a new antiplatelet strategy to mitigate thrombotic risk in diabetes and other cardiovascular diseases.
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Doenças Cardiovasculares , Endorribonucleases , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Estresse do Retículo Endoplasmático , Endorribonucleases/genética , Endorribonucleases/metabolismo , Humanos , Camundongos , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo , eIF-2 QuinaseRESUMO
Deletion of the entire gene encoding the RarA protein of Escherichia coli results in a growth defect and additional deficiencies that were initially ascribed to a lack of RarA function. Further work revealed that most of the effects reflected the presence of sequences in the rarA gene that affect expression of the downstream gene, serS. The serS gene encodes the seryl aminoacyl-tRNA synthetase. Decreases in the expression of serS can trigger the stringent response. The sequences that affect serS expression are located in the last 15 nucleotides of the rarA gene.
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Aminoacil-tRNA Sintetases , Serina-tRNA Ligase , Aminoacil-tRNA Sintetases/genética , Escherichia coli/metabolismo , Regiões Promotoras Genéticas , Serina-tRNA Ligase/genética , Serina-tRNA Ligase/metabolismoRESUMO
Platelets have been shown to be associated with pathophysiological process beyond thrombosis, demonstrating critical additional roles in homeostatic processes, such as immune regulation, and vascular remodeling. Platelets themselves can have multiple functional states and can communicate and regulate other cells including immune cells and vascular smooth muscle cells, to serve such diverse functions. Although traditional platelet functional assays are informative and reliable, they are limited in their ability to unravel platelet phenotypic heterogeneity and interactions. Developments in methods such as electron microscopy, flow cytometry, mass spectrometry, and 'omics' studies, have led to new insights. In this Review, we focus on advances in platelet biology and function, with an emphasis on current and promising methodologies. We also discuss technical and biological challenges in platelet investigations. Using coronavirus disease 2019 (COVID-19) as an example, we further describe the translational relevance of these approaches and the possible 'bench-to-bedside' utility in patient diagnosis and care.
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The RarA protein, homologous to human WRNIP1 and yeast MgsA, is a AAA+ ATPase and one of the most highly conserved DNA repair proteins. With an apparent role in the repair of stalled or collapsed replication forks, the molecular function of this protein family remains obscure. Here, we demonstrate that RarA acts in late stages of recombinational DNA repair of post-replication gaps. A deletion of most of the rarA gene, when paired with a deletion of ruvB or ruvC, produces a growth defect, a strong synergistic increase in sensitivity to DNA damaging agents, cell elongation, and an increase in SOS induction. Except for SOS induction, these effects are all suppressed by inactivating recF, recO, or recJ, indicating that RarA, along with RuvB, acts downstream of RecA. SOS induction increases dramatically in a rarA ruvB recF/O triple mutant, suggesting the generation of large amounts of unrepaired ssDNA. The rarA ruvB defects are not suppressed (and in fact slightly increased) by recB inactivation, suggesting RarA acts primarily downstream of RecA in post-replication gaps rather than in double strand break repair. Inactivating rarA, ruvB and recG together is synthetically lethal, an outcome again suppressed by inactivation of recF, recO, or recJ. A rarA ruvB recQ triple deletion mutant is also inviable. Together, the results suggest the existence of multiple pathways, perhaps overlapping, for the resolution or reversal of recombination intermediates created by RecA protein in post-replication gaps within the broader RecF pathway. One of these paths involves RarA.
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Adenosina Trifosfatases/genética , Proteínas de Bactérias/genética , Proteínas de Ligação a DNA/genética , Epistasia Genética/genética , Proteínas de Escherichia coli/genética , RecQ Helicases/genética , Dano ao DNA/genética , Reparo do DNA/genética , Replicação do DNA/genética , DNA de Cadeia Simples , Escherichia coli/genética , Exodesoxirribonucleases , Recombinação Homóloga/genética , Recombinação Genética/genética , Mutações Sintéticas Letais/genéticaRESUMO
Enhanced platelet activation has been reported in patients with essential hypertension and heart failure. The possible contribution of platelet-derived thromboxane (TX)A2 in their pathophysiology remains unclear. We investigated the systemic TXA2 biosynthesis in vivo and gene expression of its receptor TP in 22 essential hypertension patients and a mouse model of salt-sensitive hypertension. The contribution of platelet TXA2 biosynthesis on enhanced blood pressure (BP) and overload-induced cardiac fibrosis was explored in mice by treating with low-dose Aspirin, resulting in selective inhibition of platelet cyclooxygenase (COX)-1-dependent TXA2 generation. In essential hypertensive patients, systemic biosynthesis of TXA2 [assessed by measuring its urinary metabolites (TXM) reflecting predominant platelet source] was enhanced together with higher gene expression of circulating leukocyte TP and TGF-ß, vs. normotensive controls. Similarly, in hypertensive mice with prostacyclin (PGI2) receptor (IP) deletion (IPKO) fed with a high-salt diet, enhanced urinary TXM, and left ventricular TP overexpression were detected vs. normotensive wildtype (WT) mice. Increased cardiac collagen deposition and profibrotic gene expression (including TGF-ß) was found. Low-dose Aspirin administration caused a selective inhibition of platelet TXA2 biosynthesis and mitigated enhanced blood pressure, cardiac fibrosis, and left ventricular profibrotic gene expression in IPKO but not WT mice. Moreover, the number of myofibroblasts and extravasated platelets in the heart was reduced. In cocultures of human platelets and myofibroblasts, platelet TXA2 induced profibrotic gene expression, including TGF-ß1. In conclusion, our results support tailoring low-dose Aspirin treatment in hypertensive patients with unconstrained TXA2/TP pathway to reduce blood pressure and prevent early cardiac fibrosis.
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Antifibróticos/farmacologia , Anti-Hipertensivos/farmacologia , Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatias/prevenção & controle , Hipertensão Essencial/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Tromboxano A2/sangue , Adulto , Animais , Biomarcadores/sangue , Plaquetas/metabolismo , Cardiomiopatias/sangue , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Hipertensão Essencial/sangue , Hipertensão Essencial/complicações , Hipertensão Essencial/fisiopatologia , Feminino , Fibrose , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Receptores de Tromboxanos/metabolismoRESUMO
Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1.
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Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a "hot" tumor microenvironment in immunotherapy. SIGNIFICANCE: This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.
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Neoplasias Ósseas/genética , Linfócitos do Interstício Tumoral , Sarcoma de Ewing/genética , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/fisiologia , Animais , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Movimento Celular/efeitos dos fármacos , Quimiocina CCL5/biossíntese , Quimiocina CXCL10/biossíntese , Células Dendríticas/efeitos dos fármacos , Humanos , Imunoterapia , Interferons/farmacologia , Janus Quinase 1/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/metabolismo , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/mortalidade , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/imunologia , Ubiquitina Tiolesterase/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor de Interferon gamaRESUMO
The iridocorneal endothelial (ICE) syndrome is a sporadic, unilateral condition characterized by abnormalities of the cornea, anterior chamber angle, and iris affecting middle-aged women (3rd to 5th decade). It consists of three variants: progressive iris atrophy, Cogan-Reese syndrome-diffuse nevus or iris nodules, and Chandler syndrome-corneal endothelial abnormalities leading to corneal edema. This syndrome has an abnormal corneal endothelial cell layer (proliferative endotheliopathy), which migrates across the angle and onto the surface of the iris. It is a potentially blinding condition as a result of secondary glaucoma and/or corneal decompensation. Although few case reports have shown an association of ICE syndrome with macular edema; however, our case was unique in the sense that it was associated with neurosensory detachment (NSD). It can be suggested that PG analogs are not a good idea to be prescribed for secondary glaucoma management in patients with ICE syndrome as it can predispose to the development of macular edema with NSD. How to cite this article: Dubey S, Jain K, Singh S, et al. Iridocorneal Endothelial Syndrome with Coexisting Macular Edema and Neurosensory Detachment: An Unusual Case Report. J Curr Glaucoma Pract 2021;15(3):149-152.
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An iris cyst is a nonkeratinized squamous epithelial-lined space involving a layer of iris. The presentation of iris cyst can be variable-innocuous or presenting with secondary complications. The identification of whether the cyst is primary or secondary is important. The prognosis of primary iris cysts is good, as the majority does not require treatment and that of secondary iris cysts is much more capricious depending on their presentation. Their optimal management often poses a challenge for ophthalmologists. Here, we will present two cases of iris cysts with diverse presentation along with a review of the literature of this rare clinical entity.
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OBJECTIVE: Use next-generation sequencing (NGS) technology to improve our diagnostic yield in patients with suspected genetic disorders in the Asian setting. DESIGN: A diagnostic study conducted between 2014 and 2019 (and ongoing) under the Singapore Undiagnosed Disease Program. Date of last analysis was 1 July 2019. SETTING: Inpatient and outpatient genetics service at two large academic centres in Singapore. PATIENTS: Inclusion criteria: patients suspected of genetic disorders, based on abnormal antenatal ultrasound, multiple congenital anomalies and developmental delay. EXCLUSION CRITERIA: patients with known genetic disorders, either after clinical assessment or investigations (such as karyotype or chromosomal microarray). INTERVENTIONS: Use of NGS technology-whole exome sequencing (WES) or whole genome sequencing (WGS). MAIN OUTCOME MEASURES: (1) Diagnostic yield by sequencing type, (2) diagnostic yield by phenotypical categories, (3) reduction in time to diagnosis and (4) change in clinical outcomes and management. RESULTS: We demonstrate a 37.8% diagnostic yield for WES (n=172) and a 33.3% yield for WGS (n=24). The yield was higher when sequencing was conducted on trios (40.2%), as well as for certain phenotypes (neuromuscular, 54%, and skeletal dysplasia, 50%). In addition to aiding genetic counselling in 100% of the families, a positive result led to a change in treatment in 27% of patients. CONCLUSION: Genomic sequencing is an effective method for diagnosing rare disease or previous 'undiagnosed' disease. The clinical utility of WES/WGS is seen in the shortened time to diagnosis and the discovery of novel variants. Additionally, reaching a diagnosis significantly impacts families and leads to alteration in management of these patients.
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Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala , Doenças não Diagnosticadas/genética , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Lactente , Masculino , Singapura , Doenças não Diagnosticadas/diagnóstico , Adulto JovemRESUMO
Most, but not all, homologous genetic recombination in bacteria is mediated by the RecA recombinase. The mechanistic origin of RecA-independent recombination has remained enigmatic. Here, we demonstrate that the RarA protein makes a major enzymatic contribution to RecA-independent recombination. In particular, RarA makes substantial contributions to intermolecular recombination and to recombination events involving relatively short (<200 bp) homologous sequences, where RecA-mediated recombination is inefficient. The effects are seen here in plasmid-based recombination assays and in vivo cloning processes. Vestigial levels of recombination remain even when both RecA and RarA are absent. Additional pathways for RecA-independent recombination, possibly mediated by helicases, are suppressed by exonucleases ExoI and RecJ. Translesion DNA polymerases may also contribute. Our results provide additional substance to a previous report of a functional overlap between RecA and RarA.
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Adenosina Trifosfatases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Recombinação Homóloga/genética , Recombinases Rec A/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/genética , DNA Helicases/metabolismo , Reparo do DNA/genética , DNA Bacteriano/genética , Exodesoxirribonucleases/genéticaRESUMO
The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.