Rapamycin induces transactivation of the EGFR and increases cell survival.

The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway

Long-term Outcomes of Small Pigmented Choroidal Melanoma Treated with Primary Photodynamic Therapy

PURPOSE: To report the long-term outcomes of patients with small, pigmented posteriorly located choroidal melanoma undergoing primary treatment using photodynamic therapy (PDT) with verteporfin at the London Ocular Oncology Service. DESIGN: Retrospective interventional consecutive case series SUBJECTS: All patients undergoing primary treatment using PDT with verteporfin from April 2014 and December 2015 and followed until December 2019. METHODS: This is a long-term follow up study of the same cohort of patients previously reported by our group in 2017 and 2018. MAIN OUTCOME MEASURE: Local tumor control, visual outcomes and metastasis-free survival. RESULTS: Twenty-six patients were included with a mean (± SD) age and tumour thickness of 62 ± 14 years and 1.3 ± 0.5 mm, respectively. Tumours were posteriorly located (mean distance to optic nerve and fovea = 2.0 ± 2.2 and 1.6 ± 1.5 mm, respectively) and the majority were fully pigmented (73%). Overall, patients were followed for a median [IQR, range] of 49.5 [15.3, 7.0 - 66.0] months from first PDT to last follow up. Over the course of this study, 14/26 (54%) have developed a local recurrence at a median of 20.0 months [20.5, 4.7 - 60.9 months]. The most common pattern of recurrence was an isolated increase in basal dimensions (9/14; 64%). Median [IQR] final LogMAR visual acuity of the whole cohort was 0.2 [0.5]. The only statistically significant difference in baseline and outcome characteristics between treatment failures and non-failures was distance to fovea (median [IQR]: 0.5 [1.3] versus 2.5 [2.8]; P = 0.002) and final LogMAR visual acuity (median [IQR]: 0.50 [0.80] versus 0.00 [0.14]; P-value = 0.002), respectively. CONCLUSIONS: While treatment of small pigmented posterior choroidal melanoma with PDT effectively preserves visual acuity, five-year treatment-success calculated by Kaplan-Meier analysis was only 38.4%. Recurrences after PDT tend to occur along the tumor edges, often with minimal increase in thickness. Given the substantial risk of treatment failure, primary PDT with vertepofrin is recommended in exceptional cases of choroidal melanoma, where other treatments with greater tumor control are not a feasible option

Characterizing Triviality of the Exponent Lattice of A Polynomial through Galois and Galois-Like Groups

The problem of computing \emph{the exponent lattice} which consists of all the multiplicative relations between the roots of a univariate polynomial has drawn much attention in the field of computer algebra. As is known, almost all irreducible polynomials with integer coefficients have only trivial exponent lattices. However, the algorithms in the literature have difficulty in proving such triviality for a generic polynomial. In this paper, the relations between the Galois group (respectively, \emph{the Galois-like groups}) and the triviality of the exponent lattice of a polynomial are investigated. The \bbbq\emph{-trivial} pairs, which are at the heart of the relations between the Galois group and the triviality of the exponent lattice of a polynomial, are characterized. An effective algorithm is developed to recognize these pairs. Based on this, a new algorithm is designed to prove the triviality of the exponent lattice of a generic irreducible polynomial, which considerably improves a state-of-the-art algorithm of the same type when the polynomial degree becomes larger. In addition, the concept of the Galois-like groups of a polynomial is introduced. Some properties of the Galois-like groups are proved and, more importantly, a sufficient and necessary condition is given for a polynomial (which is not necessarily irreducible) to have trivial exponent lattice.Comment: 19 pages,2 figure

Exploring the Depths of Health Literacy Are We Teaching This and Why Does It Matter?

Background: Why does Health Literacy Matter? Healthcare practitioners often work with older persons with low health literacy without realizing that this issues limiting the success of their interventions. They may also lack awareness of the serious impact that low health literacy can have, since it is associated with lower reported health status, increased hospitalizations, and increased morbidity (Levasseur & Carrier, 2011). The current US healthcare system places increase demands on consumers to manage their own health (Smith & Gutman, 2011). Educators in the health professions must instill a sense of responsibility in future practitioners to understand the important role they play in promoting health literacy. Students in the health professions must acquire the tools necessary to empower their older adult and other clients using health literacy principles. Poster presented at the 65th annual scientific meeting of Gerontological Society of America in San Diego, California

Primary photodynamic therapy with verteporfin for pigmented posterior pole cT1a choroidal melanoma: a 3-year retrospective analysis

AIMS: To investigate the outcomes of primary photodynamic therapy (PDT) for pigmented posterior pole cT1a choroidal melanoma. METHODS: Retrospective interventional consecutive case series of 26 patients (26 eyes) with pigmented posterior pole cT1a choroidal melanoma, who were treated with 3 sessions of PDT and followed-up thereafter. RESULTS: Included were 11 males and 15 females that presented at a median age of 66 years (mean: 64) with transformed naevi (n=11) or suspicious lesions (n=15) with ≥3 risk factors for growth, with lipofuscin in all. In all cases, diagnosis was clinically based (no tissue biopsy). Tumour control was achieved in 16 (62%) patients in a median follow-up time of 29 months (mean: 27). Ten patients failed treatment by form of radial expansion, diagnosed in a median time of 13 months (mean: 12) from last treatment. By Kaplan-Meier analysis, success rate after 1, 2 and 3 years was 85%, 59% and 51%, respectively. On statistical analysis, number of suspicious features was found to be the only risk factor predicting failure (P=0.046). One patient developed macula-sparing branch retinal artery occlusion after treatment. Following PDT, subretinal fluid resolved in all cases and visual acuity significantly improved in all treatment-success cases (P=0.043). There were no cases of metastatic spread. CONCLUSION: Primary PDT resulted in tumour regression of small, pigmented choroidal melanoma in 62% after a mean of 27 months. Treatment was more effective in tumours with three or less risk factors for growth, and resulted with fluid elimination and significant improvement in vision in treatment-success cases

Long-term sequel of posterolateral rotatory instability of the elbow: a case report

The natural course of untreated posterior lateral rotatory instability of the elbow is unclear. A case of elbow arthrosis with progressing deformity and flexion contracture after an episode of elbow dislocation about 20 years ago presented the possibility the long term outcome of untreated posterior lateral rotatory instability of the elbow

Primary intraocular lymphoma.

Primary intraocular lymphoma (PIOL) is an ocular malignancy that is a subset of primary central system lymphoma (PCNSL). Approximately one-third of PIOL patients will have concurrent PCNSL at presentation, and 42-92% will develop PCNSL within a mean of 8-29 months. Although rare, the incidence has been rising in both immunocompromised and immunocompetent populations. The majority of PIOL is diffuse large B-cell lymphoma, though rare T-cell variants are described. Recently, PIOL has been classified by main site of involvement in the eye, with vitreoretinal lymphoma as the most common type of ocular lymphoma related to PCNSL. Diagnosis remains challenging for ophthalmologists and pathologists. PIOL can masquerade as noninfectious or infectious uveitis, white dot syndromes, or occasionally as other neoplasms such as metastatic cancers. Laboratory diagnosis by cytology has been much aided by the use of immunocytochemistry, flow cytometry, biochemical finding of interleukin changes (IL10:IL6 ratio > 1), and cellular microdissection with polymerase chain reaction amplification for clonality. Use of several tests improves the diagnostic yield. Approaches to treatment have centered on systemic methotrexate-based chemotherapy, often with cytarabine (Ara-C) and radiotherapy. Use of intravitreal chemotherapy with methotrexate (0.4 mg/0.1 mL) is promising in controlling ocular disease, and intravitreal rituximab (anti-CD20 monoclonal antibody) has also been tried. Despite these advances, prognosis remains poor

Outcomes of intravitreal methotrexate to salvage eyes with relapsed primary intraocular lymphoma

PURPOSE: To report the outcomes of intravitreal methotrexate (MTX) injections to rescue eyes with relapsed primary intraocular lymphoma (PIOL). METHODS: Retrospective case series of patients with ocular relapse of PIOL who had initially received systemic chemotherapy (all five cases) and external beam radiotherapy (EBRT) to brain and orbits (two cases). Injections of MTX (400 µg/0.1 mL) were given one time per week for 1 month, every other week for 4 months, followed by a maintenance phase of one injection one time per month for 8 months (total of 20 injections in a year). RESULTS: From April 2008 to February 2016, there were nine eyes of five patients (three men; average age at first presentation 62 years) treated with our rescue protocol of intravitreal MTX injections. Ocular relapse occurred at a mean interval of 15 months (range 5-34 months) after the completion of initial systemic treatment. At mean follow-up of 31 months (range 5-104 months), tumour control was achieved in eight out of nine eyes (89%); one eye failed, with persistent retinal infiltrates despite increasing the frequency of injections, resulting in severe keratopathy. The only other complication occurred in one eye, developing cystoid macular oedema from MTX injections that resolved with topical anti-inflammatory medications and reduced frequency of MTX. There were no cases of reduced vision or ocular relapse, but two patients died (one of central nervous system lymphoma). CONCLUSIONS: Intravitreal MTX was a safe and effective treatment modality for relapsed PIOL after systemic chemotherapy and radiotherapy, achieving local tumour control in 89%, and hence represents an optimal choice. However, given the rare nature of PIOL, larger collaborative studies with longer follow-up are needed to corroborate this