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To investigate the clinical features and surgical outcomes of rhegmatogenous retinal detachment (RRD) associated with giant retinal tears (GRTs) at a tertiary referral center. A retrospective, non-consecutive interventional case series of GRT-associated RRDs that underwent primary surgical repair at the University of Michigan W.K. Kellogg Eye Center between January 1, 2011 and July 1, 2020. Clinical characteristics and preoperative, perioperative, and postoperative data were collected. Forty-eight eyes of 47 patients with GRT-associated RRDs met inclusion criteria, including those that were children (under 12 years, N=4, 8.3%), associated with a history of trauma (N=20, 41.7%) or with grade C proliferative vitreoretinopathy (PVR-C) (N=7, 14.6%) at baseline. Median age was 46 years (interquartile range (IQR): 29 years, range: 4 to 72 years), median follow-up was 28 months (IQR: 43 months, range: 3-124 months), and 83.3% (N=40) of subjects were male. Primary surgical repair for GRT-associated RRDs included pars plana vitrectomy (PPV) (N=40, 83.3%), scleral buckle (SB) (N=1, 2.1%), or combined PPV/SB (N=7, 14.6%). Surgical approach commonly involved the use of perfluorocarbon liquid (N=43, 90%) and gas tamponade (N=39, 81%). Single surgery anatomic success (SSAS) was 75% (95% CI: 60%, 85%) at 3 months and 65% (95 CI: 47%, 78%) at 2 years. Final anatomic success was achieved in all 48 eyes (100%). Median visual acuity improved from 20/250 preoperatively to 20/60 at final follow-up, with 44% (N=20) of eyes achieving postoperative visual acuity of 20/40 or better. In this series from a tertiary referral center, both complex and non-complex GRT-associated RRDs were most commonly managed with PPV alone, perfluorocarbon liquid, and gas tamponade with favorable final anatomic and visual outcomes comparable to other modern GRT series.

Parkinson’s disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.Parkinson’s disease brain neurons exhibit a widespread epigenetic dysregulation of enhancers that is linked to an upregulation of TET2. Inactivation of TET2 protects against nigral dopaminergic neuronal loss and neuroinflammation.

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse NF1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. NF1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of NF1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of NF1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST⁺ and PV⁺ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

BACKGROUND AND OBJECTIVE: To investigate the effect of the coronavirus disease 2019 (COVID-19) lockdown on the presentation and management of acute, primary rhegmatogenous retinal detachment (RRD). PATIENTS AND METHODS: This was a single-center, consecutive case series with historic controls, examining patients during the COVID-19 “stay-at-home” order (March 24 to June 1, 2020), the subsequent reopening phase (June 1 to July 31, 2020), and corresponding preceding intervals (March 24 to July 31, 2016 to 2019). RESULTS: Despite a significant increase in patients presenting with macula-off RRD during the COVID-19 lockdown compared to the 2016 to 2019 timeframe (P = .03), the rate of single surgery anatomical success was similar between all groups (P = .66), as was final visual acuity (P = .61). No delays between presentation and surgical intervention were observed during the lockdown (P = .49). CONCLUSIONS: Despite the limitations of the COVID-19 lockdown, patients underwent surgery in a timely manner and achieved comparable visual outcomes to controls before COVID-19. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:593–600.]

Concentric macular rings (CMRs) of Henle's fiber layer (HFL) are an uncommon imaging phenomenon previously associated with foveal hypoplasia and epiretinal membrane. Here, we present a case of a 15-year-old boy with bilateral CMRs, normal visual function, and no ocular pathology. These bilateral findings in the absence of vitreomacular traction, foveal hypoplasia, or any other ocular abnormality suggest that macular rings may occur as a normal but rare variant of HFL architecture. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:353–355.]

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2 Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2 Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2 Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms. Signals through VEGF receptor 2 (VEGFR2) increase vascular permeability, promoting cancer progression. Here the authors show that a point mutation in VEGFR2 preventing its auto-phosphorylation leads to reduced metastatic spread and improved response to chemotherapy in tumor-bearing mice, without affecting tumor inflammation.

Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA. We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients. The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively). The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

The project MarParCloud (Marine biological production, organic aerosol Particles and marine Clouds: a process chain) aims to improve our understanding of the genesis, modification and impact of marine organic matter (OM) from its biological production, to its export to marine aerosol particles and, finally, to its ability to act as ice-nucleating particles (INPs) and cloud condensation nuclei (CCN). A field campaign at the Cape Verde Atmospheric Observatory (CVAO) in the tropics in September–October 2017 formed the core of this project that was jointly performed with the project MARSU (MARine atmospheric Science Unravelled). A suite of chemical, physical, biological and meteorological techniques was applied, and comprehensive measurements of bulk water, the sea surface microlayer (SML), cloud water and ambient aerosol particles collected at a ground-based and a mountain station took place. Key variables comprised the chemical characterization of the atmospherically relevant OM components in the ocean and the atmosphere as well as measurements of INPs and CCN. Moreover, bacterial cell counts, mercury species and trace gases were analyzed. To interpret the results, the measurements were accompanied by various auxiliary parameters such as air mass back-trajectory analysis, vertical atmospheric profile analysis, cloud observations and pigment measurements in seawater. Additional modeling studies supported the experimental analysis. During the campaign, the CVAO exhibited marine air masses with low and partly moderate dust influences. The marine boundary layer was well mixed as indicated by an almost uniform particle number size distribution within the boundary layer. Lipid biomarkers were present in the aerosol particles in typical concentrations of marine background conditions. Accumulation- and coarse-mode particles served as CCN and were efficiently transferred to the cloud water. The ascent of ocean-derived compounds, such as sea salt and sugar-like compounds, to the cloud level, as derived from chemical analysis and atmospheric transfer modeling results, denotes an influence of marine emissions on cloud formation. Organic nitrogen compounds (free amino acids) were enriched by several orders of magnitude in submicron aerosol particles and in cloud water compared to seawater. However, INP measurements also indicated a significant contribution of other non-marine sources to the local INP concentration, as (biologically active) INPs were mainly present in supermicron aerosol particles that are not suggested to undergo strong enrichment during ocean–atmosphere transfer. In addition, the number of CCN at the supersaturation of 0.30 % was about 2.5 times higher during dust periods compared to marine periods. Lipids, sugar-like compounds, UV-absorbing (UV: ultraviolet) humic-like substances and low-molecular-weight neutral components were important organic compounds in the seawater, and highly surface-active lipids were enriched within the SML. The selective enrichment of specific organic compounds in the SML needs to be studied in further detail and implemented in an OM source function for emission modeling to better understand transfer patterns, the mechanisms of marine OM transformation in the atmosphere and the role of additional sources. In summary, when looking at particulate mass, we see oceanic compounds transferred to the atmospheric aerosol and to the cloud level, while from a perspective of particle number concentrations, sea spray aerosol (i.e., primary marine aerosol) contributions to both CCN and INPs are rather limited.

Senile plaques comprised of Aβ peptides are a hallmark of Alzheimer’s disease (AD) brain, as are activated glia that release inflammatory molecules, including eicosanoids. Previous studies have demonstrated that amyloid precursor protein (APP) and Aβ levels can be increased through activation of thromboxane A2-prostanoid (TP) receptors on neurons. We demonstrate that TP receptor regulation of APP expression depends on Gα q -signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gα q -linked prostaglandin E2 and leukotriene D4 receptors also regulate APP expression. Prostaglandin E2 and thromboxane A2, as well as total APP levels, were found to be elevated in the brains of aged 5XFAD transgenic mice harboring Aβ plaques and activated glia, suggesting that increased APP expression resulted from eicosanoid binding to Gα q -linked neuronal receptors. Notably, inhibition of eicosanoid synthesis significantly lowered brain APP protein levels in aged 5XFAD mice. These results provide new insights into potential AD therapeutic strategies.

The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro . In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP–CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP–CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.