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Purpose: To study the long-term outcomes of lacrimal canalicular trephination (LCT) with viscoelastic-assisted monocanalicular stenting (VAMS) for the treatment of epiphora secondary to lacrimal canalicular obstructions (LCO). Methods: Our study was a retrospective interventional work. All patients diagnosed with LCO, having morbid epiphora (Munk's scale ≥ 2), were included. The LCO was divided as proximal (< 6mm from punctum) and distal (≥ 6mm from punctum). Sisler's lacrimal trephine (21 gauge) was used to recanalize the LCO with monocanalicular stent (0.64mm diameter) insertion, which was kept for a minimum of 6 weeks and a post-stent removal follow-up of 12 months was ensured. Fluorescein dye disappearance test and lacrimal irrigation were used as functional and anatomical tests for evaluation, respectively. Results: We included 73 eyes of 52 patients having a mean age of 44.5 years. Of the total, the proximal LCO was seen in 38 eyes (52.1%) and distal in 35 eyes (47.9%). The preoperative Munk's score of 5 was noted in the majority (n=57 eyes, 78.1%). The majority (n=32 eyes, 43.8%) had chronic blepharitis or meibomian gland disease as etiology. Monocanalicular stent was kept in place for a mean of 13.5 weeks. At a mean follow-up of 14.5 months, complete response was noted in 35.6% cases, while 50.7% had partial and 13.7% had a failure of the procedure. Conclusions: LCT (without DCR) is a minimally invasive, simple, and effective technique for the treatment of LCO in the long term. VAMS is a helpful innovation to facilitate the insertion of the flexible silicone stent., (© The Authors.Romanian Society of Ophthalmology.)

Small interfering RNA (siRNA)-based therapy has been subject of intense research since the discovery of RNA interference (RNAi), providing a tool to potentially silence any chosen gene. Nevertheless, efficient delivery still presents a major hurdle to translating this promising technology into medical practice. Here, we describe a straightforward method to prepare and characterize an effective delivery system consisting of low-molecular-weight polyethylenimine (PEI) and transferrin (Tf). Tf-PEI polyplexes are not only able to successfully transport and protect the sensitive nucleic acid payload from degradation but also to selectively deliver the siRNA to transferrin receptor (TfR)-overexpressing cells, playing key roles in the pathology of numerous cancer types as well as inflammatory diseases.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease with unknown etiology and poor prognosis. IPF patients die within 2 years after diagnosis mostly due to respiratory failure. Current treatments against IPF aim to ameliorate patient symptoms and to delay disease progression. Unfortunately, therapies targeting the causes of or reverting IPF have not yet been developed. Here we show that reduced levels of miRNA lethal 7d (MIRLET7D) in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we find that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduces fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model), and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition.

Purpose: To evaluate the outcomes of pars plana vitrectomy (PPV) with microscope-integrated intraoperative optical coherence tomography (I-OCT)-guided traction removal and center-sparing internal limiting membrane (cs-ILM) peeling., Methods: Nine eyes with myopic traction maculopathy as diagnosed on SD-OCT underwent PPV with I-OCT-guided cs-ILM peeling and were evaluated prospectively for resolution of central macular thickness (CMT) and improvement in best-corrected visual acuity (BCVA), and complications, if any, were noted. All patients were followed up for more than 9 months., Results: Resolution of the macular retinoschisis was seen in all nine eyes on SD-OCT. At 36 weeks, there was a significant improvement in mean BCVA from the preoperative BCVA (P = 0.0089) along with a reduction in the CMT from 569.77 ± 263.19 to 166.0 ± 43.91 um (P = 0.0039). None of the eyes showed worsening of BCVA or development of full-thickness macular hole in the intraoperative or follow-up period., Conclusion: PPV with I-OCT-guided cs-ILM peeling helps in complete removal of traction, resolution of retinoschisis and good functional recovery with low intraoperative and postoperative complications.

The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which are important regulators of different nuclear processes by controlling chromatin structure. However, the full extent of ncRNA function has remained elusive. Here we deciphered the function of the microRNA Mirlet7d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7d binds ncRNAs expressed from these genes. Mirlet7d-ncRNA duplexes are further bound by C1D, which in turn targets the RNA exosome complex and the polycomb repressive complex 2 (PRC2) to the bidirectionally active loci. The exosome degrades the ncRNAs, whereas PRC2 induces heterochromatin and transcriptional silencing through EZH2. Moreover, this multicomponent RNA-protein complex, which we named MiCEE, tethers the regulated genes to the perinucleolar region and thus is required for proper nucleolar organization. Our study demonstrates that the MiCEE complex mediates epigenetic silencing of bidirectionally expressed genes and global genome organization.

Background: To determine the frequency of CYP1B1 p.E229K and p.R368H, gene mutations in a cohort of sporadic juvenile onset open-angle glaucoma (JOAG) patients and to evaluate their genotype/phenotype correlation., Methods: Unrelated JOAG patients whose first-degree relatives had been examined and found to be unaffected were included in the study. The patients and their parents were screened for p.E229K and p.R368H mutations. The phenotypic characteristics were compared between probands carrying the mutations and those who did not carry these mutations., Results: Out of 120 JOAG patients included in the study, the p.E229K mutation was seen in 9 probands (7.5%) and p.R368H in 7 (5.8%). The average age of onset of the disease (p = 0.3) and the highest untreated IOP (p = 0.4) among those carrying mutations was not significantly different from those who did not have these mutations. The proportion of probands with angle dysgenesis among those with p.E229K and p.R368H mutations was 70% (11 out of 16) in comparison to 65% (67 out of 104) of those who did not harbour these mutations (p = 0.56). Similarly, the probands with moderate to high myopia among those with p.E229K and p.R368H mutations was 20% (3 out of 16) in comparison to 18% (18 out of 104) of those who did not harbour these mutations (p = 0.59)., Conclusion: The frequency of p.E229K and p.R368H mutations of the CYP1B1 gene is low even among sporadic JOAG patients. Moreover, there is no clinical correlation between the presence of these mutations and disease severity.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Early LC diagnosis is crucial to reduce the high case fatality rate of this disease. In this case-control study, we developed an accurate LC diagnosis test using retrospectively collected formalin-fixed paraffin-embedded (FFPE) human lung tissues and prospectively collected exhaled breath condensates (EBCs). Following international guidelines for diagnostic methods with clinical application, reproducible standard operating procedures (SOP) were established for every step comprising our LC diagnosis method. We analyzed the expression of distinct mRNAs expressed from GATA6 and NKX2-1, key regulators of lung development. The Em/Ad expression ratios of GATA6 and NKX2-1 detected in EBCs were combined using linear kernel support vector machines (SVM) into the LC score, which can be used for LC detection. LC score-based diagnosis achieved a high performance in an independent validation cohort. We propose our method as a non-invasive, accurate, and low-price option to complement the success of computed tomography imaging (CT) and chest X-ray (CXR) for LC diagnosis., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)

Lung cancer is the leading cause of cancer-related deaths worldwide. The initiation and progression of lung cancer is the result of the interaction between permanent genetic and dynamic epigenetic alterations. DNA methylation is the best studied epigenetic mark in human cancers. Altered DNA methylation in cancer was identified in 1983. Within 30 years of this discovery, DNA methylation inhibitors are used clinically to treat a variety of cancers, highlighting the importance of the epigenetic basis of cancer. In addition, histone modifications, nucleosome remodeling, and micro RNA (miRNA)-mediated gene regulation are also fundamental to tumor genesis. Distinct chromatin alterations occur in all stages of lung cancer, including initiation, growth, and metastasis. Therefore, stage-specific epigenetic changes can be used as powerful and reliable tools for early diagnosis of lung cancer and to monitor patient prognosis. Moreover, since epigenetic changes are dynamic and reversible, chromatin modifiers are promising targets for the development of more effective therapeutic strategies against cancer. This review summarizes the chromatin alterations in lung cancer, focusing on the diagnostic and therapeutic approaches targeting epigenetic modifications that could help to reduce the high case-fatality rate of this dreadful disease.