Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-kB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-kB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides in vitro. CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLRmediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. Significance: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone.

Purpose To assess the relationship between parental smoking and childhood refractive errors in Singapore Chinese children aged 6-72 months recruited through the STrabismus, Amblyopia, and Refractive errors in Singaporean children study. Methods A total of 4164 children were recruited, with a positive response rate of 72.3% (n ¼ 3009). Cycloplegic refraction measurements were obtained from all children by trained eye professionals. Parents underwent an interviewer-administered questionnaire with information on demographics, lifestyle, and parental smoking history being obtained. Results Spherical equivalent readings were obtained for 87.7% of the children. In all, 52.1% were male (n ¼ 1375). The overall prevalence of myopia (at least À 0.5 D) was 11.0%. Overall, 37.1% of the fathers interviewed gave a history of smoking. Among the mothers interviewed, 9.2% gave a history of smoking, 6.6% had smoked during the child's life, and 2.2% had smoked during the pregnancy. Maternal history of ever smoking, smoking during child's life, and smoking during pregnancy were associated with decreased odds ratio (OR) of childhood myopia (OR 0.50 (P ¼ 0.01), OR 0.39 (P ¼ 0.01), and OR 0.3 (P ¼ 0.14), respectively). Paternal history of smoking was associated with decreased OR of childhood myopia (OR of 0.72 (P ¼ 0.02)). Conclusion In light of this finding of an inverse association between parental smoking and childhood myopia, further studies are suggested to better understand the role of nicotinic acetylcholine receptor pharmacology in ocular development. This may pave the way for the development of targeted treatment strategies for prevention of myopia.

Prolonged visually stressful activities aggravate dry eye disease (DED). The duration spent on such activities and their relationship with DED clinical features were investigated. Patients completed an activity log as they performed their usual activities over 1 typical rest day and 1 typical work day. The log included time spent in an air-conditioned environment, windy environment, driving, watching television, computer use, reading, watching a movie in the theatre, and wearing contact lens. Average daily activity hours were calculated and correlated with clinical features of DED. Thirty-five logs were returned. Positive correlation was found between watching television and episodic blurred vision (P < 0.01). Computer use was negatively correlated with episodic blur vision, burning sensation, and gritty sensation (P < 0.05). Negative correlation was found between time spent in windy environments, driving, reading, and certain DED symptoms (P < 0.05). Reading correlated positively with severity of corneal fluorescein staining and reduced Schirmer's values (P < 0.03). The use of air conditioning correlated negatively with episodic blur vision but positively with visual blurring that improves with lubricants (P = 0.02). This study is the first to evaluate the relationship between time spent on DED-aggravating activities and DED clinical features. Negative correlations between certain activities and DED symptoms suggest an unconscious modification of lifestyle to alleviate symptoms.

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.

Objective:The aim was to compare the visual, refractive, topographic and biomechanical outcomes in patients with progressive keratoconus treated with either conventional or accelerated crosslinking at one year follow up.Methods:It is a prospective, non-randomised interventional study of 76 patients who underwent conventional (CXL; 3mW/cm2 for 30 minutes) or accelerated cross linking (KXL; 30mW/cm2 for 4 minutes) for progressive keratoconus. Baseline and postoperative visual acuity, manifest refraction, corneal topography, pachymetry, endothelial cell density and biomechanical parameters of corneal hysteresis and corneal resistance factor were evaluated and compared.Results:The 2 groups were comparable in terms of uncorrected and best corrected visual acuity and spherical equivalent. Both groups showed no significant increase in K1, K2 and Kmean from baseline at 12 months. There was also no difference between the CXL and KXL group for postoperative corneal topography as well as central and minimal pachymetry up to 12 months. There was a significant increase in both corneal hysteresis (0.62mm Hg, P=0.04) and corneal resistance factor (0.91mm Hg, P=0.003) in the KXL group at 12 months but not in the CXL group. There was no significant endothelial cell loss throughout follow up in both the groups.Conclusion:We have established comparability of the 2 protocols in stabilizing the progression of keratoconus. Our findings also suggested an added biomechanical advantage of accelerated crosslinking at 1 year follow up.

Purpose of review A process is ongoing to produce a definition of glaucomatous optic neuropathy (GON) using quantitative, objective data from structural and functional tests. At present, a common practice is to define GON by subjective features said to be ‘characteristic’ as judged by those experienced in glaucoma care. Recent findings An objective definition would standardize the comparison of clinical research results across studies, without precluding simultaneous use of idiosyncratic definitions in the same reports. To achieve this goal, expert opinion was solicited to reach optimal agreement on one or more consensus, GON definitions. An interactive period of online discussion by 176 international experts led to 110 responses in an online survey that narrowed possible definitional structures into testable criteria. Summary Two approaches to validation of one or more sets of criteria for definite and possible GON are ongoing. The general principles include definition for each eye individually, inclusion of a borderline category, no intraocular pressure criterion, and both structural and functional defects in appropriate physical locations. Each validation approach uses clinician diagnosis as a standard against which objective criteria are compared, with the initial approach using a three-level categorical scale, and the second approach using 0--100 scaling.

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Intraocular inflammatory eye disease is one of the important causes of ocular morbidity. Even though the prevalence of uveitis is less common in relation to diabetic retinopathy, glaucoma or age related macular degeneration, the complexity and heterogeneity of the disease makes it more unique. Putative uveitogenic retinal antigens incite innate immunity by the process of antigen mimicry and have been shown to be associated in patients with intraocular inflammatory disease by numerous experimental studies. Laboratory diagnostic tools to aid the etiologic association in intraocular inflammatory disease have evolved over the last two decades and we are entering into an era of molecular diagnostic tests. Sophisticated novel technologies such as multiplex bead assays to assess biological signatures have revolutionized the management of complex refractory uveitis. Nevertheless, there is still a long way to go to establish the causal relationship between these biomarkers and specific uveitic entities. Experimental studies have shown the supreme role of infliximab in the management of Behcet's disease. Despite significant experimental and case control studies, the deficiency of randomized clinical trials using these biologic agents has handicapped us in exploring them as a front line therapy in severe refractory uveitis. Studies still need to answer the safety of these potentially life threatening drugs in a selected group of patients and determine when to commence and for how long the treatment has to be given. This review article covers some basic concepts of cytokines in uveitis and their potential application for therapy in refractory uveitis.